790:-NH and the side chain OH of Thr-315, the amido-NH and side chain carboxylate of Glu-286 and the amido carbonyl with the backbone NH of the Asp-381. The anilino segment of nilotinib has close binding interactions with Met-318, Phe-317 and Thr-315 residues of a region within the ATP binding site. The remaining half of the compound extends beyond the Thr-315 gatekeeper residue to bind within an additional pocket. The 3-methylimidazole and trifluoro-methyl groups of nilotinib make important interactions with the Abl kinase domain. These groups also make the shape of nilotinib very different from that of imatinib. Nilotinib also binds to the kinase through a large number of weak van der Waals interactions.
808:
1029:
substance with satisfactory pharmacokinetics, but now with reduced potency against T315I also. The first step in increasing the potency again was to look at other TKI's. Imatinib has a terminal methyl piperazine group which has been shown to form a hydrogen bond with the carbonyl oxygen atom of residue Ile-360 in the activation loop of the Abl kinase. The piperazine ring is also a common solubilizing group that could further improve the pharmacokinetic properties of the molecule. Those speculations were confirmed with a two-fold increase in inhibitory action against Bcr-Abl T315I mutated kinase and the silver lining was the
799:
nilotinib and a steric clash between the isoleucine-methyl group and 2-methylphenyl phenyl group of nilotinib. On the other hand, resistance to nilotinib is associated with a limited spectrum of Bcr-Abl kinase mutations that mostly affect the P-loop and T315I. However all mutations except T315I were effectively suppressed by increasing nilotinib concentration. Although nilotinib is more potent than imatinib it is possible that its specific mode of binding to Abl may make other sites vulnerable to new kinds of drug resistance.
1164:
the core allowed a number of conformations of the substances to bind to the ATP site of the Abl kinase, though all of them bound to the kinase's active form. Further study of the binding showed that the position of the sulfur that binds to the toluene structure played an important role in regard to Abl binding and also that only one of the nitrogen's one thiadiazole formed a hydrogen bond. Furthermore, computer analysis of the structure showed the amide connected benzene-ketone could be substituted for a more favorable
1152:
885:
also not a substrate of multidrug P-glycoprotein efflux pumps like imatinib. Because of this dasatinib may be active in some patients after failure with both imatinib and nilotinib. Although dasatinib is much more potent than imatinib it is possible, like with nilotinib, that its specific mode of binding to Abl may lead to new vulnerable sites that could confer new kinds of drug resistance. Mutations have been found on Phe317 so that is a potential vulnerable site for this drug.
1046:
288:
25:
658:). OCT1 plays a significant role in imatinib resistance by inhibiting its influx and thus decreasing the intracellular bioavailability of imatinib. Patients with low expression, activity or polymorphisms of OCT1 had significantly lower intracellular levels of imatinib. The response of patients with low OCT1 activity was significantly dose-dependent. This data indicates that OCT1 activity is an important determinant in the molecular response to imatinib.
1071:
Despite, or even because of this, ponatinib is a potent drug and targets not just most of the known mutations on the Bcr-Abl TK but, most importantly of all, T315I. This mutation is emerging as a common pathway to failure of both first and second line treatments. Unlike other T315I targeting inhibitors in development, ponatinib does not target Aurora kinases, which clearly distinguishes it from them and emphasizes the significance of its discovery.
840:
983:
236:
762:
865:
only. Compounds that target the active conformation have been identified but the binding site in all the hundreds of human protein kinases is very similar. Therefore, there is a considerably greater scope for dissimilarities between the inactive conformations so the efforts to discover highly selective kinase inhibitors are being directed towards molecules that bind to the inactive conformation.
1360:
1240:
937:). Bosutinib's activity was first described in 2001 and it was disclosed as an Abl kinase inhibitor in 2003. At first it was believed that bosutinib was a selective Src kinase inhibitor but now it is known that its kinase inhibition profile is far less restricted than originally thought. Bosutinib inhibits Src, Abl and a wide range of both tyrosine and serine-threonine kinases.
1390:
1300:
1270:
1181:-benzene falls nicely into a hydrophobic pocket created by Val 256, Ala 253, Lys 271 and Ala 380. Whilst the similar binding properties to those of dasatinib, suggests the possibility of producing Bcr-Abl TKI's from thiazole cores is real, the question remains open whether this research will just lead to a dasatinib analog or a novel way to inhibit TKs.
899:
1330:
458:
798:
Nilotinib has shown effect against most mutations (32/33) that are associated with imatinib resistance but the T315I mutant remains resistant to nilotinib. Its ineffectiveness against the T315I mutant seems to be a consequence of the loss of an H-bond interaction between threonine-O and aniline-NH on
666:
In a few patient groups, resistance may be caused by the activation of other signaling pathways, particularly the Src family kinases. The Src family kinases have been implicated in Bcr-Abl signaling and mediate imatinib resistance by stabilizing the active conformation of Bcr-Abl, a conformation that
1163:
that commercially available thiadiazole derivatives displayed moderate inhibitory action on both Abl and Src kinases. Using a 1,3,4 thiadiazol core and trying different groups or molecules on the benzene rings, several different substances with inhibitory properties were produced. The flexibility of
1131:
Bafetinib has its place in TKI therapy as it is effective both against most imatinib resistant mutations (not including T315I) and some dasatinib resistant mutations. Bafetinib also has more affinity for Bcr-Abl than nilotinib (but less than dasatinib) but only targets Bcr-Abl and Src family kinases
1105:
substituents. Finally a trifluoromethyl group at position 3 was found to give the best results, with approximately 36-fold improvement over imatinib. The addition of a hydrophobic group now needed to be countered to sustain the solubility of the substance. Closer examination of the crystal structure
473:
within the Bcr-Abl kinase domain that interfere with imatinib binding. Bcr-Abl independent mechanisms include factors influencing the concentration of imatinib within the cell, for example by alterations in drug influx and efflux and activation of Bcr-Abl independent pathways, such as members of the
1418:
Imatinib remains a standard frontline TKI. Nilotinib and dasatinib are also approved by the FDA as frontline drugs, in June and
October 2010, respectively. Four of these drugs, nilotinib, dasatinib, bosutinib and ponatinib are approved for the treatment of imatinib-resistant or intolerant CML. The
1127:
Due to the structural similarities of imatinib and bafetinib, their binding to Bcr-Abl is also quite similar. The only notable difference comes from the hydrophobic interaction between the trifluoromethyl group and the hydrophobic pocket created by Ile-293, Leu-298, Leu-354, and Val-379. This group
884:
Since dasatinib is an inhibitor of Src family kinases, it can overcome resistance due to Src family kinase activation. Because it does not bind to Bcr-Abl with the same stringent conformational requirements as imatinib, it can inhibit all Bcr-Abl kinase domain mutants except for T315I. Dasatinib is
514:
can cause amino acid substitutions inside the kinase domain of the Bcr-Abl protein and disrupt the binding site of imatinib on the tyrosine kinase, resulting in a loss of sensitivity to the drug. These mutations normally affect the structure of the Bcr-Abl protein, leading either to interruption of
2452:
Huang, W.; Zhu, X.; Wang, Y.; Azam, M.; Wen, D.; Sundaramoorthi, R.; Thomas, R.; Liu, S.; Banda, G.; Lentini, S. P.; Das, S.; Xu, Q.; Keats, J.; Wang, F.; Wardwell, S.; Ning, Y.; Snodgrass, J. T.; Broudy, M. I.; Russian, K.; Daley, G. Q.; Iuliucci, J.; Dalgarno, D. C.; Clackson, T.; Sawyer, T. K.;
1092:
In the search for a substance that fit the criteria mentioned, the crystal structure of imatinib bound to Abl was examined. This revealed a hydrophobic pocket around the phenyl ring adjacent to the piperazinylmethyl group of imatinib. Attempts to utilize this pocket to increase efficacy led to the
1004:
group on C6 on the purine core was found to display both satisfactory pharmacokinetics and efficacy. Finally modifications on the diarylamide side chain by adding imidazole appendages were inspired by then newly released nilotinib structure. Those modifications resulted in what was called AP24163.
990:
Ariad used the highly potent drug lead, AP23464 to further investigate inhibitory possibilities of purine cored templates for dual Src/Abl inhibitors. First, searching for substances effective on the inactive conformation of Abl, the side chain bound to the nitrogen on the purine core was replaced
864:
Dasatinib binds to Abl with less stringent conformational requirements than imatinib so it exhibits increased potency but reduced selectivity compared to imatinib. Dasatinib binds both the active and inactive conformation of Abl kinase, contrary to the binding of most other TKIs to the active form
1168:
ring. Though it has to be noted this analysis was done with comparing the crystal structure of Abl and dasatinib, which is the inactive conformation of Abl, the knowledge gathered from the docking and structure analysis led to identification of a compound, referred to as substance 14, with a high
749:
activity of imatinib and nilotinib has been reported following coadministration. This might be a result of the fact that the drugs are taken up in cells by different mechanisms: imatinib influx is dependent on OCT1 but nilotinib is not. Nilotinib is also not a substrate for the efflux transporter
445:
milestones. Patients that fail to achieve defined responses at predefined time points are described as primarily resistant to therapy, and those losing previously obtained milestones in disease regression are termed secondarily resistant. Before a conclusion is drawn, it is important to consider
436:
with resistance to the drug. This was rapidly followed by the clinical description of imatinib resistant cells in patients, which has resulted in efforts to better understand the biology behind these observations. Assessments of therapeutic response of imatinib in patients with CML are based upon
1066:
linkage forms favorable van der Waals interactions with the amino acid and the trifluoromethyl group binds to a pocket induced by the inactive conformation kinase. Also in the conformation of the kinase that ponatinib rests in, additional favorable van der Waals interactions between the drug and
1028:
reaction; but the pharmacokinetics were still poor. When developing AP24163, adding a cyclopropane side chain on C8 in the purine core resulted in favorable pharmacokinetics. Several different side chains were then tested, but the best results were obtained with no side chain at all, resulting a
2527:
O'Hare, T.; Shakespeare, W.; Zhu, X.; Eide, C.; Rivera, V.; Wang, F.; Adrian, L.; Zhou, T.; Huang, W.; Xu, Q.; Metcalf Ca, C. A.; Tyner, J. W.; Loriaux, M. M.; Corbin, A. S.; Wardwell, S.; Ning, Y.; Keats, J. A.; Wang, Y.; Sundaramoorthi, R.; Thomas, M.; Zhou, D.; Snodgrass, J.; Commodore, L.;
2488:
Huang, W. S.; Metcalf, C. A.; Sundaramoorthi, R.; Wang, Y.; Zou, D.; Thomas, R. M.; Zhu, X.; Cai, L.; Wen, D. (2010). "Discovery of 3-pyridazin-3-yl)ethynyl]-4-methyl-N-{4--3-(trifluoromethyl)phenyl}benzamide (AP24534), a Potent, Orally Active Pan-Inhibitor of
Breakpoint Cluster Region-Abelson
1070:
With this structure ponatinib has been shown to have a relatively broad kinase specificity profile which can probably be linked to the linearity of the linkage section of the molecule. With this linear structure the drug appears to avoid steric clashes with hydrophobic TK gatekeeper residues.
625:
and the activation loop. These loops have specific arrangements in the inactive conformation of Bcr-Abl that stabilize the basal conformation. Mutations in these loops destabilize arrangement of the loops such that the kinase domain cannot assume the inactive conformation required for imatinib
679:
patients may include strategies such as increasing the dose of imatinib or the use of second-generation drugs. Escalation of imatinib-doses has shown to overcome some cases of primary resistance to imatinib, such as Bcr-Abl duplication, but the response is usually short acting. In the case of
202:
Due to increasing resistance and intolerance to imatinib efforts were made to develop new drugs that could inhibit the Bcr-Abl tyrosine kinase. This led to the discovery of second generation drugs. While drug screening was used to develop imatinib, second generation TKI's were developed with
1110:
pyrimidine ring was substituted for the pyridine, which was found to increase solubility while leaving efficacy the same or even slightly greater. Finally to improve the hydrogen bonding of the piperazine ring of imatinib with Ile-360 and His-361, pyrrolidine and azetidine derivatives were
729:
is a phenylamino-pyrimidine derivative that is structurally related to imatinib. It was developed based on the structure of the Abl-imatinib complex to address the need associated with imatinib intolerance and resistance. Small changes were made on the imatinib molecule to make it more
2402:
O'Hare, T.; Pollock, R.; Stoffregen, E. P.; Keats, J. A.; Abdullah, O. M.; Moseson, E. M.; Rivera, V. M.; Tang, H.; Metcalf Ca, C. A.; Bohacek, R. S.; Wang, Y.; Sundaramoorthi, R.; Shakespeare, W. C.; Dalgarno, D.; Clackson, T.; Sawyer, T. K.; Deininger, M. W.; Druker, B. J. (2004).
604:
to the binding of most TKIs. When discovered, it was estimated that every 6 out of 9 cases of advanced stage CML with imatinib resistance carried this mutation. T315I produces the highest magnitude of resistance of any mutation both to imatinib and second generations TKIs.
2727:
Radi, M.; Crespan, E.; Botta, G.; Falchi, F.; Maga, G.; Manetti, F.; Corradi, V.; Mancini, M.; Santucci, M.; Schenone, S.; Botta, M. (2008). "Discovery and SAR of 1,3,4-thiadiazole derivatives as potent Abl tyrosine kinase inhibitors and cytodifferentiating agents".
680:
resistance or intolerance, it could be helpful to test for Bcr-Abl mutations to direct the choice of second line treatment as the variable options have different function profile against the different mechanisms of resistance. Second-generation drugs offer improved
1067:
Tyr-253 and Phe-382. Five hydrogen bonds are generated, with the backbone of Met-318 in the hinge region, with the backbone of Asp-381, with the side chain of Glu-286 and the protonated methylpiperazine with the backbone-carbonyl atoms of Ile-360 and His-361.
945:
Bosutinib inhibited cells expressing a variety of mutations, some of which led to imatinib resistance, but the T315 mutation was completely resistant to bosutinib. In contrast to imatinib, nilotinib and dasatinib, bosutinib is not an efficient substrate for
165:
Bcr-Abl TKIs are also being investigated as potential disease-modifying treatments for
Parkinsonβs disease. While initial results have shown modest efficacy, further studies involving highly potent representatives of this drug class are necessary.
2776:
Manetti, F.; Falchi, F.; Crespan, E.; Schenone, S.; Maga, G.; Botta, M. (2008). "N-(thiazol-2-yl)-2-thiophene carboxamide derivatives as Abl inhibitors identified by a pharmacophore-based database screening of commercially available compounds".
1005:
During this development cycle, Ariad tested several substances against cells transfected with T315I mutated Bcr-Abl kinase and, surprisingly, found AP24163 demonstrated reasonable inhibitory action on top of potent inhibition of native Bcr-Abl.
626:
binding. Mutations in the P-loop region are the most common, accounting for 36-48% of all mutations. There are clinical data indicating that Bcr-Abl mutations in the P-loop is 70-100 fold less sensitive to imatinib compared with native Bcr-Abl.
1822:
Manley, P.; Stiefl, N.; Cowan-Jacob, S.; Kaufman, S.; Mestan, J.; Wartmann, M.; Wiesmann, M.; Woodman, R.; Gallagher, N. (2010). "Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib".
999:
group on the purine core clashed with a glycine rich P-loop in that confirmation and was thus removed from the molecule. Then with in-vitro testing on inhibitory activity and in-vivo oral absorption assays a more lipophilic, amide bound,
1083:
was the offspring of an attempt to create a more potent drug than imatinib, with efficacy against various point mutations in the Bcr-Abl kinase, with fewer adverse effects and with narrower kinase spectra, namely just Lyn and Bcr-Abl.
973:
analogs. The substance potently inhibits, on nanomolar scale, Src and Bcr-Abl kinases including many common imatinib resistant Bcr-Abl mutations. AP23464 does not inhibit the T315I mutation, however, whereas AP24534 (ponatinib) does.
835:
and is 325-fold more potent against cells expressing wild type Bcr-Abl than imatinib. Dasatinib is a multi targeted inhibitor of Bcr-Abl and Src family kinases. It also has inhibitory activity against additional downstream kinases.
2577:
Kimura, S.; Naito, H.; Segawa, H.; Kuroda, J.; Yuasa, T.; Sato, K.; Yokota, A.; Kamitsuji, Y.; Kawata, E.; Ashihara, E.; Nakaya, Y.; Naruoka, H.; Wakayama, T.; Nasu, K.; Asaki, T.; Niwa, T.; Hirabayashi, K.; Maekawa, T. (2005).
1198:(ABL001) is an inhibitor of the Abelson kinase targeting the myristoyl pocket to allosterically inhibit the enzyme. As of August 2020, it had completed a phase III study in CML (ASCEMBL) showing superior efficacy to bosutinib.
2627:
Horio, T.; Hamasaki, T.; Inoue, T.; Wakayama, T.; Itou, S.; Naito, H.; Asaki, T.; Hayase, H.; Niwa, T. (2007). "Structural factors contributing to the Abl/Lyn dual inhibitory activity of 3-substituted benzamide derivatives".
968:
The road to discovery can be linked to AP23464, one of the first of Ariad's ATP competitive dual Src/Abl inhibitors. AP23464 was identified using structure base drug design and focused synthetic libraries of trisubstituted
1192:(DCC-2036) Also an inhibitor of TIE-2 and VEGFR-2. It has had a phase 1 clinical trial for Leukemias (Ph+ CML With T315I Mutation). It is in a phase 1 clinical trial of combination therapy for metastatic breast cancer.
704:
Second generation drugs are intended to have decreased resistance and intolerance than imatinib. Second generation drugs that are currently marketed are nilotinib, dasatinib, bosutinib and ponatinib (third generation).
186:
encodes a constitutively activated kinase. Drug discovery that specifically targeted the ATP binding site of a single kinase was regarded as quite a challenging task since hundreds of protein kinases were known in the
311:
binding site and the activation-loop adopts a conformation in which it occludes the substrate binding site and disrupts the ATP phosphate binding site to block the catalytic activity of the enzyme. The shift of the
2849:
1033:
of the substance (named '19a') appeared to have decreased, allowing for smaller doses with the same potency. Whilst '19a' exhibited good oral pharmacokinetics in both mice and rats, it also retained high
474:
Src kinase family. Imatinib resistance can also be produced by other mechanisms that will not be mentioned here as the importance of those mechanisms still remain a question due to lack of clinical data.
995:
structure, that was known to have a high affinity to the inactive conformation by forming crucial hydrogen bonds and filling hydrophobic pockets on the kinase. Furthermore, it was determined that the
1038:
at 6.69. So, in attempts to reduce the molecule's lipophilicity further, substitution of a single carbon atom on the imidazopyridine core was made; which resulted in what is now known as the compound
1475:
An, X.; Tiwari, A.; Sun, Y.; Ding, P.; Ashby Jr, C.; Chen, Z. (2010). "BCR-ABL tyrosine kinase inhibitors in the treatment of
Philadelphia chromosome positive chronic myeloid leukemia: a review".
1774:
Manley, P.; Cowan-Jacob, S.; Mestan, J. (2005). "Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia".
1858:
Mahon (August 1, 2000). "Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: Diverse mechanisms of resistance".
1177:
The binding of substance 14 is partly similar to dasatinib, the aminothiazole segment of substance 14 makes a bi-dentate H-bonding interaction with the backbone CO and NH of Met-318 while the
2663:
Deguchi, Y.; Kimura, S.; Ashihara, E.; Niwa, T.; Hodohara, K.; Fujiyama, Y.; Maekawa, T. (2008). "Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines".
1106:
of imatinib-kinase complex revealed Tyr-236 was in close proximity to the pyridine ring of imatinib, suggesting there was little or no room for a larger group there. With that in mind a more
1716:
Asaki, T.; Sugiyama, Y.; Hamamoto, T.; Higashioka, M.; Umehara, M.; Naito, H.; Niwa, T. (2006). "Design and synthesis of 3-substituted benzamide derivatives as Bcr-Abl kinase inhibitors".
2257:
Tokarski, J. S.; Newitt, J. A.; Chang, C. Y.; Cheng, J. D.; Wittekind, M.; Kiefer, S. E.; Kish, K.; Lee, F. Y.; Borzillerri, R.; Lombardo, L. J.; Xie, D.; Zhang, Y.; Klei, H. E. (2006).
1012:
of the molecule into the ATP binding site of T315I mutated Bcr-Abl kinase revealed that the expected steric clash with isoleucine was not present due to a lesser sterically demanding
1510:
Gosch Berton, Giovanni; Cyntia Lima
Fonseca Rodrigues, Amanda; dos Santos Borges, Rafael; Rodrigues Cardoso, Nicole; de Oliveira, Thiago AbrahΓ£o; Oliveira Marques, Marcos VinΓcius.
634:
Additional mechanisms have been postulated to describe resistance seen in various model systems although none have been clearly identified as a sole source of clinical resistance.
410:-methyl group of imatinib. At the time of its discovery, in the absence of structural information, no clear explanation for the impressive selectivity of imatinib could be found.
925:
groups, led to the discovery of bosutinib. It was suggested to be an Abl kinase inhibitor and when tested as such it turned out to be slightly more potent against Abl than Src (
2065:
Chatterjee, S.; Sanjeev, B.S. (2023). "Community detection in
Epstein-Barr virus associated carcinomas and role of tyrosine kinase in etiological mechanisms for oncogenesis".
1575:
Manley, P.W., Cowan-Jacob, S. W., Buchdunger, E., Fabbro, D., Fendrich, G., Furet, P., Meyer, T. and
Zimmermann, J. (2002). "Imatinib: a selective tyrosine kinase inhibitor".
1016:
linkage between the purine core and the diarylamide side chain compared to other TKIs. The first step was to try to find an even less sterically demanding structure. First an
1557:
Bixby, D., Talpaz, M. (2009). "Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance".
876:
segment of dasatinib makes a bi-dentate H-bonding interaction with the backbone CO and NH of Met-318 and the amide-NH makes an H-bond with the side chain oxygen of Thr-315.
2453:
Shakespeare, W. C. (2009). "9-(Arenethenyl)purines as dual Src/Abl kinase inhibitors targeting the inactive conformation: design, synthesis, and biological evaluation".
2919:
227:(Gleevec) was discovered in 1992 and is regarded as first generation drug since it is the first Bcr-Abl tyrosine kinase inhibitor to be used in the treatment of CML.
515:
critical contact points between the drug and the Bcr-Abl protein or induction of a conformational change, resulting in a protein that imatinib is unable to bind to.
667:
does not bind imatinib. Furthermore, increasing evidence suggests that Src family kinases are also involved in Bcr-Abl-independent forms of imatinib resistance.
428:
is the main drive in continuing research and development of Bcr-Abl TKI. Shortly after the introduction of imatinib, investigators began to describe a number of
413:
Although first-generation treatment achieved an extremely high response rate and a low relapse rate in CML patients, some patients do experience resistance or
465:
In general, imatinib resistance can be subdivided into Bcr-Abl dependent and independent mechanisms. Bcr-Abl dependent mechanisms include over expression or
1419:
first-line data for these compounds are encouraging and suggest that some or all of them may replace imatinib as a frontline standard TKI in the future.
527:
523:
499:, leading to higher expression of the pathogen. Increasing the imatinib dose could surmount this kind of resistance, provided that severe or intolerable
2259:"The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants"
174:
CML has a well defined molecular target and relatively selective therapies aimed at that target, which is not the case for the majority of cancers and
1511:
1604:
Druker, B. J. and Lydon, N. B. (2000). "Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia".
1895:
Stein, B., Smith, B.D. (2010). "Treatment
Options for Patients With Chronic Myeloid Leukemia Who Are Resistant to or Unable to Tolerate Imatinib".
2698:
1120:
807:
782:
interactions and thus blocks its catalytic activity. Nilotinib binds to the kinase domain by making four hydrogen bond interactions involving the
734:
and selective as a Bcr-Abl inhibitor and these changes resulted in the discovery of nilotinib. Nilotinib is a selective Bcr-Abl kinase inhibitor.
714:
688:
that administration of multiple Abl kinase inhibitors in early phase patients could be used to delay or prevent the emergence of drug resistant
613:
was approved in 2013 for use as second-line CML treatment, and is the only licensed TKI which binds to the T315I mutated kinase successfully.
2530:"AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance"
1639:
Eck, M.; Manley, P. (2009). "The interplay of structural information and functional studies in kinase drug design: insights from BCR-Abl".
1512:"Abelson Tyrosine Kinase Inhibitors in Parkinson's Disease and Lewy Body Dementia: A Systematic Review, Meta-analysis, and Meta-regression"
2356:
Boschelli, F.; Arndt, K.; Gambacorti-Passerini, C. (2010). "Bosutinib: a review of preclinical studies in chronic myelogenous leukaemia".
2390:
1008:
Following up on that breakthrough Ariad began further research to increase the efficacy of compound AP24163 against the T315I mutation.
2850:"Novartis investigational novel STAMP inhibitor asciminib (ABL001) meets primary endpoint of Phase III chronic myeloid leukemia study"
2405:"Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML"
466:
950:
that promotes efflux of foreign molecules from cells. Bosutinib even inhibits these transporter proteins in higher concentrations.
868:
Dasatinib has some structural elements in common with nilotinib, in particular the juxtaposition of the aminopyrimidine and the
642:
Some investigations in cell lines have shown that imatinib resistance may be partly due to an increase in the expression of the
646:
efflux pump. By utilizing agents that inhibit P-glycoprotein activity imatinib susceptibility has been restored in some cases.
2580:"NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia"
2173:
Breccia, M.; Alimena, G. (2010). "Nilotinib: a second-generation tyrosine kinase inhibitor for chronic myeloid leukemia".
1128:
can also be linked to bafetinib's specificity for Lyn, as the binding site there is almost identical to that on Bcr-Abl.
133:-alpha (rIFN-Ξ±) were utilized. Even though the first Bcr-Abl TK inhibitor was named "the magic bullet" to cure cancer by
676:
519:
110:
67:
1062:
core rests in the adenine pocket of the enzyme. The methylphenyl group occupies a hydrophobic pocket behind I315, the
534:
mutations and the T315I mutation. Mutations on other sites of the kinase have also been reported, for example on the C-
70:(CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called
2914:
272:
965:, an orally active Bcr-Abl TKI effective against the T315I mutation had been approved for a phase II clinical trial.
323:
results in the exposure of a binding pocket which can be utilized by inhibitors. This conformation is referred to as
1079:
With the emerging resistance to imatinib treatment after its launch alternative treatment was highly sought after.
248:
1588:
Shawver, L. K., Slamon, D. and
Ullrich, A. (2002). "Smart drugs:Tyrosine kinase inhibitors in cancer therapy".
1024:
linkage was selected. To achieve this linkage an imidazolpyridine core was used as a starting material for a
2811:
832:
755:
737:
Nilotinib is 10-30 fold more potent than imatinib in inhibiting activity of the Bcr-Abl tyrosine kinase and
71:
2210:"Dasatinib impairs long-term expansion of leukemic progenitors in a subset of acute myeloid leukemia cases"
1020:
linkage was tested, that resulted in higher potency but unfavorable pharmacokinetics. Later, a more stable
684:
and a greater likelihood of success in resistant patients. There is also a growing interest in testing the
2824:
Study Safety and
Preliminary Efficacy of DCC-2036 in Patients With Leukemias (Ph+ CML With T315I Mutation)
1143:
Some interest has been with thiazol and thiadiazole derivatives and their ability to inhibit Bcr-Abl TKs.
1030:
731:
681:
308:
303:
of Abl only when the domain adopts the inactive or "closed" conformation. This is where the glycine-rich,
276:
1435:
Nowell, Peter; Hungerford, David (1960). "A minute chromosome in human chronic granulocytic leukaemia".
1035:
958:
751:
610:
457:
451:
296:
2865:"Standard treatment of Ph+ CML in 2010: how, when and where not to use what BCR/ABL1 kinase inhibitor?"
1160:
921:
as an Src inhibitor. Combination of the features of this hit and a related compound, and attachment of
1058:
X-ray crystallographic analysis of ponatinib and T315I Bcr-Abl mutated kinase display that the imidazo
558:
The T315I is a unique mutation because of its resistance to all approved Bcr-Abl inhibitors, prior to
1025:
268:
1151:
1009:
934:
930:
387:
1132:
Lck and Lyn; with unrivalled specificity which suggests the probability of fewer adverse effects.
741:
of Bcr-Abl expressing cells. The drug effectively inhibits the auto phosphorylation of Bcr-Abl on
2609:
2434:
2090:
1940:
917:
template. Src kinase dependent yeast screening led to characterization of a 4-anilino-3-quinoline
244:
208:
195:
is prevented and Bcr-Abl expressing cells either have a selective growth disadvantage or undergo
159:
147:
63:
1911:"Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification"
1909:
Gorre, M.; Mohammed, M.; Ellwood, K.; Hsu, N.; Paquette, R.; Rao, P. N.; Sawyers, C. L. (2001).
1045:
338:
Bcr-Abl complex and prevents ATP from reaching its binding site. The hydrogen bonds involve the
287:
2909:
2886:
2794:
2755:
2680:
2645:
2601:
2559:
2506:
2470:
2426:
2373:
2331:
2280:
2239:
2190:
2148:
2082:
2047:
1981:
1932:
1875:
1840:
1791:
1733:
1691:
1656:
1527:
1492:
1021:
693:
689:
139:
magazine, a second generation of Bcr-Abl TKI was subsequently developed to combat the initial
1620:
Buchanan, S. G. (2003) "Protein structure: discovering selective protein kinase inhibitors".
2876:
2786:
2745:
2737:
2672:
2637:
2591:
2549:
2541:
2498:
2462:
2416:
2365:
2321:
2311:
2270:
2229:
2221:
2182:
2138:
2074:
2037:
2027:
1971:
1922:
1867:
1832:
1783:
1725:
1683:
1648:
1519:
1484:
1111:
introduced. The most promising substance from these final modifications was labeled NS-187.
754:
molecular structures of these two drugs might look similar, they are dissimilar in terms of
696:
involved in CML may significantly improve response rates and potentially increase survival.
488:
414:
2837:
Rebastinib Plus Antitubulin Therapy With Paclitaxel or Eribulin in Metastatic Breast Cancer
1135:
CytRx has bafetinib in phase II clinical trial as a treatment for leukemia as of May 2010.
1119:
839:
713:
1063:
511:
500:
470:
425:
320:
192:
179:
140:
135:
2528:
Sawyer, T. K.; Dalgarno, D. C.; Deininger, M. W. N.; Druker, B. J.; Clackson, T. (2009).
271:
as a kinase inhibitor remained the same. Subsequently, introducing a methyl substituent
38:
Please help update this article to reflect recent events or newly available information.
2554:
2529:
2326:
2299:
2234:
2209:
2042:
2015:
947:
778:
Nilotinib binds to the inactive conformation of the Abl kinase domain, largely through
643:
601:
343:
300:
175:
155:
151:
1960:"Active transport of imatinib into and out of cells: implications for drug resistance"
982:
102:) and a constitutively active Bcr-Abl tyrosine kinase that has been implicated in the
2903:
2881:
2864:
2094:
873:
844:
828:
779:
597:
447:
371:
367:
331:
313:
260:
91:
2613:
235:
2699:"CytRx Initiates Phase 2 Clinical Trial with Bafetinib in Advanced Prostate Cancer"
2438:
2016:"Nilotinib for the treatment of chronic myeloid leukemia: An evidence-based review"
1944:
1001:
996:
761:
496:
188:
103:
83:
75:
2835:
2822:
2676:
2275:
2258:
2186:
2078:
1488:
106:
of CML. Compounds have been developed to selectively inhibit the tyrosine kinase.
1787:
1687:
1523:
1013:
914:
869:
738:
654:
The entry of imatinib into cells is dependent on an organic cation transporter (
438:
391:
263:
and was then tested and modified to develop imatinib. With a replacement of the
204:
183:
126:
2790:
2741:
2641:
2596:
2579:
2421:
2404:
2369:
1976:
1959:
1729:
2545:
2225:
1836:
1652:
1107:
1059:
922:
685:
586:
571:
546:
lobe. Some of these mutations have clinical significance, but none as much as
543:
539:
433:
407:
395:
379:
375:
351:
347:
256:
130:
1871:
1531:
495:
that encodes for the pathogenic Bcr-Abl tyrosine kinase is duplicated in the
267:
group with a benzamido group, the compound's specificity increased while its
2143:
2126:
1927:
1910:
1382:
1359:
1352:
1322:
1292:
1262:
1195:
1165:
1080:
1039:
1017:
962:
910:
906:
852:
820:
766:
726:
606:
579:
559:
442:
383:
359:
264:
196:
118:
2890:
2798:
2759:
2684:
2649:
2605:
2563:
2510:
2474:
2430:
2377:
2335:
2284:
2243:
2194:
2152:
2086:
2051:
1985:
1936:
1879:
1844:
1795:
1737:
1695:
1660:
1496:
1239:
247:
of Bcr-Abl tyrosine kinase played a limited role because it was unknown. A
158:, or the constitutive activation of downstream signaling molecules such as
2750:
1232:
1102:
1094:
848:
824:
783:
742:
592:
at that position - thus 'T315I'. This substitution eliminates a critical
563:
429:
363:
355:
339:
335:
252:
224:
122:
114:
95:
87:
79:
117:, no drugs were available to alter the natural progression of CML. Only
2316:
1178:
1098:
918:
787:
746:
655:
567:
487:
The first reports of resistance to imatinib described a development of
399:
316:
99:
2502:
2466:
1389:
1329:
1299:
1269:
898:
621:
The structure of Bcr-Abl contains two flexible loops, the ATP-binding
2032:
970:
622:
593:
547:
531:
403:
304:
1674:
Mandal, S.; Moudgil, M.; Mandal, S. (2009). "Rational drug design".
454:
in CML patients and this could lead to undesired clinical outcomes.
154:, over-expression of Bcr-Abl, increased production of transmembrane
1118:
1044:
981:
897:
838:
760:
712:
575:
535:
456:
286:
234:
255:
was performed to identify a starting molecule, which was called "
178:
today. Bcr-Abl was regarded as highly attractive target for drug
992:
926:
492:
765:
Crystal structure of Abl kinase domain (blue) in complex with
18:
1776:
Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
78:
in 1960 and is a consequence of fusion between the Abelson (
675:
The treatment options for imatinib resistant or intolerant
578:'315' of the Abl protein) sequence resulting in amino acid
518:
Mutational frequencies appear to increase as the disease,
2489:(BCR-ABL) Kinase Including the T315I Gatekeeper Mutant".
2208:
Han, L.; Schuringa, J.; Mulder, A.; Vellenga, E. (2010).
1958:
Thomas, J.; Wang, L.; Clark, R.; Pirmohamed, M. (2004).
1093:
addition of various hydrophobic groups including single
913:
scaffold and is structurally related to the AstraZeneca
831:
salt. It was discovered with a program directed towards
191:. In the presence of TKI the binding of ATP is blocked,
600:
between imatinib and the Abl kinase, and also creates
1398:
Met-318, Thr-315, Glu-286, Asp-381, His-361, Ile-360
1248:
Met-318, Thr-315, Glu-286, Asp-381, Ile-380, His-361
692:. The combination of two agents targeting different
2127:"Dasatinib: a new step in molecular target therapy"
750:P-glycoprotein pump, unlike imatinib. Although the
1155:Proposed binding site interactions of substance 14
2300:"Dasatinib in chronic myeloid leukemia: a review"
450:data has showed a high incidence of imatinib non-
2351:
2349:
2347:
2345:
2014:Jabbour, E.; Cortes, J.; Kantarjian, H. (2009).
299:have revealed that imatinib binds to the kinase
2120:
2118:
2116:
2114:
2112:
2110:
2108:
2106:
2104:
2771:
2769:
2168:
2166:
2164:
2162:
2009:
2007:
2005:
2003:
2001:
1999:
1997:
1995:
1769:
1767:
1616:
1614:
1159:One Italian research group discovered through
574:substitution at position 944 of the Abl gene (
542:, substrate binding site, activation loop and
1817:
1815:
1813:
1811:
1809:
1807:
1805:
1765:
1763:
1761:
1759:
1757:
1755:
1753:
1751:
1749:
1747:
8:
2779:Bioorganic & Medicinal Chemistry Letters
2730:Bioorganic & Medicinal Chemistry Letters
2630:Bioorganic & Medicinal Chemistry Letters
2522:
2520:
1891:
1889:
1718:Bioorganic & Medicinal Chemistry Letters
1711:
1709:
1707:
1705:
1600:
1598:
1571:
1569:
1567:
1368:Met-318, Asp-381, Glu-286, His-381, Ile-380
1139:1,3,4 thiadiazole derivatives - Substance 14
961:, Inc. announced on September 10, 2010 that
630:Bcr-Abl Independent mechanisms of resistance
406:-379 around the phenyl ring adjacent to the
275:to the pyrimidinyl-amino group enhanced the
2722:
2720:
1553:
1551:
1549:
1547:
1545:
1543:
1541:
745:-177 that is involved in CML pathogenesis.
650:Drug import by organic cation transporter 1
2869:European Journal of Clinical Investigation
478:Bcr-Abl dependent mechanisms of resistance
2880:
2749:
2595:
2553:
2420:
2325:
2315:
2304:Therapeutics and Clinical Risk Management
2274:
2233:
2142:
2041:
2031:
1975:
1926:
1634:
1632:
1630:
1470:
319:(DFG) triad at the N-terminal end of the
1468:
1466:
1464:
1462:
1460:
1458:
1456:
1454:
1452:
1450:
1205:
1150:
806:
662:Alternative signaling pathway activation
2920:Non-receptor tyrosine kinase inhibitors
1427:
948:multidrug resistance (MDR) transporters
786:-N and the backbone NH of Met-318, the
530:. The most important mutations are the
461:Common mechanisms of resistance to TKIs
207:approach due to increased knowledge in
390:interactions contribute to binding. A
370:-286, the carbonyl and backbone-NH of
146:New forms of resistance can arise as:
2298:Aguilera, Dolly G (31 October 2006).
1606:The journal of Clinical Investigation
638:Drug efflux caused by P-glycoproteins
330:Imatinib binds to Abl domain via six
239:Evolution of Pyrimidine A to imatinib
74:. This abnormality was discovered by
7:
1825:Bioorganic & Medicinal Chemistry
758:structure and molecular properties.
378:with the backbone-carbonyl atoms of
243:In the development of imatinib, the
2125:Olivieri, A.; Manzione, L. (2007).
1278:Met-318, Thr-315, Glu-286, Asp-381
362:-315, the amide-NH and side chain
334:interactions. This stabilizes the
56:Bcr-Abl tyrosine-kinase inhibitors
14:
2882:10.1111/j.1365-2362.2010.02328.x
1676:European Journal of Pharmacology
1518:: 10.1097/WNF.0000000000000597.
1407:Marketed as second line therapy
1388:
1377:Marketed as second line therapy
1358:
1347:Marketed as second line therapy
1328:
1317:Marketed as second line therapy
1298:
1287:Marketed as second line therapy
1268:
1238:
386:-361. Additionally, a number of
211:of the Bcr-Abl tyrosine kinase.
23:
1641:Current Opinion in Cell Biology
1257:Marketed as first line therapy
2491:Journal of Medicinal Chemistry
2455:Journal of Medicinal Chemistry
259:A". This compound served as a
1:
2677:10.1016/j.leukres.2007.11.008
2276:10.1158/0008-5472.CAN-05-4187
2187:10.1016/j.leukres.2009.08.031
2079:10.1016/j.micpath.2023.106115
1489:10.1016/j.leukres.2010.04.016
1123:Bafetinib in its binding site
1049:Ponatinib in its binding site
986:Ponatinib development history
811:Dasatinib in its binding site
717:Nilotinib in its binding site
86:and the break point cluster (
1788:10.1016/j.bbapap.2005.07.040
1688:10.1016/j.ejphar.2009.06.065
1524:10.1097/WNF.0000000000000597
562:. It is caused by a single
291:Imatinib in its binding site
111:Food and Drug Administration
68:chronic myelogenous leukemia
1414:Current status - re Ph+ CML
909:'s structure is based on a
374:-381, the protonated methyl
2936:
2791:10.1016/j.bmcl.2008.06.082
2742:10.1016/j.bmcl.2007.11.112
2642:10.1016/j.bmcl.2007.03.002
2597:10.1182/blood-2005-06-2209
2422:10.1182/blood-2004-05-1851
2370:10.1016/j.ejca.2010.02.032
2358:European Journal of Cancer
1977:10.1182/blood-2003-12-4276
1730:10.1016/j.bmcl.2005.11.042
1577:European Journal of Cancer
1516:Clinical Neuropharmacology
94:, resulting in a chimeric
82:) tyrosine kinase gene at
2546:10.1016/j.ccr.2009.09.028
2226:10.1007/s00277-010-0948-7
1837:10.1016/j.bmc.2010.08.026
1653:10.1016/j.ceb.2009.01.014
251:of chemical libraries at
249:high-throughput screening
32:This article needs to be
16:Pharmaceutical drug class
1872:10.1182/blood.V96.3.1070
825:thiazolylaminopyrimidine
469:of the Bcr-Abl gene and
307:(P-loop) folds over the
305:P-binding phosphate loop
297:crystallographic studies
1928:10.1126/science.1062538
851:(blue) in complex with
833:immunosuppressive drugs
700:Second generation drugs
72:Philadelphia chromosome
66:for most patients with
2067:Microbial Pathogenesis
1218:H-bonding amino acids
1156:
1124:
1050:
1031:plasma protein binding
987:
903:
856:
812:
803:Dasatinib (BMS-354825)
770:
718:
489:oncogene amplification
462:
292:
240:
150:within the Abl kinase
2144:10.1093/annonc/mdm223
1897:Clinical Therapeutics
1404:Rational drug design
1374:Rational drug design
1344:Rational drug design
1314:Rational drug design
1284:Rational drug design
1221:Binding confirmation
1154:
1122:
1048:
1036:partition coefficient
985:
959:ARIAD Pharmaceuticals
901:
842:
810:
764:
716:
585:being substituted by
550:and T315I mutations.
460:
290:
238:
109:Before the 2001 U.S.
2391:http://www.ariad.com
2214:Annals of Hematology
1075:Bafetinib (INNO-406)
596:molecule needed for
394:pocket is formed by
205:rational drug design
2863:Valent, P. (2010).
954:Ponatinib (AP24534)
889:Bosutinib (SKI-606)
843:Crystal structure (
483:Bcr-Abl duplication
2915:Medical treatments
2705:. 7 September 2010
2317:10.2147/tcrm.s3425
2131:Annals of Oncology
1227:Status as of 2017
1157:
1125:
1051:
988:
904:
857:
813:
771:
719:
709:Nilotinib (AMN107)
522:, progresses from
503:are not produced.
463:
402:-298, Leu-354 and
398:residues Ile-293,
293:
241:
209:structural biology
182:since the Bcr-Abl
160:Src-family kinases
148:missense mutations
113:(FDA) approval of
64:first-line therapy
2785:(15): 4328β4331.
2665:Leukemia Research
2636:(10): 2712β2717.
2590:(12): 3948β3954.
2503:10.1021/jm100395q
2467:10.1021/jm900166t
2461:(15): 4743β4756.
2364:(10): 1781β1789.
2269:(11): 5790β5797.
2175:Leukemia Research
1970:(12): 3739β3745.
1921:(5531): 876β880.
1831:(19): 6977β6986.
1483:(10): 1255β1268.
1477:Leukemia Research
1411:
1410:
1308:Met-318, Thr-315
1169:affinity to Abl.
1161:digital screening
849:Abl kinase domain
827:developed as the
220:Imatinib (STI571)
53:
52:
2927:
2895:
2894:
2884:
2860:
2854:
2853:
2846:
2840:
2833:
2827:
2820:
2814:
2809:
2803:
2802:
2773:
2764:
2763:
2753:
2736:(3): 1207β1211.
2724:
2715:
2714:
2712:
2710:
2695:
2689:
2688:
2660:
2654:
2653:
2624:
2618:
2617:
2599:
2574:
2568:
2567:
2557:
2524:
2515:
2514:
2485:
2479:
2478:
2449:
2443:
2442:
2424:
2415:(8): 2532β2539.
2399:
2393:
2388:
2382:
2381:
2353:
2340:
2339:
2329:
2319:
2295:
2289:
2288:
2278:
2254:
2248:
2247:
2237:
2205:
2199:
2198:
2170:
2157:
2156:
2146:
2122:
2099:
2098:
2062:
2056:
2055:
2045:
2035:
2033:10.2147/CE.S6003
2011:
1990:
1989:
1979:
1955:
1949:
1948:
1930:
1906:
1900:
1893:
1884:
1883:
1855:
1849:
1848:
1819:
1800:
1799:
1771:
1742:
1741:
1724:(5): 1421β1425.
1713:
1700:
1699:
1671:
1665:
1664:
1636:
1625:
1618:
1609:
1602:
1593:
1586:
1580:
1573:
1562:
1555:
1536:
1535:
1507:
1501:
1500:
1472:
1445:
1444:
1432:
1392:
1362:
1332:
1302:
1272:
1242:
1206:
617:P-loop mutations
602:steric hindrance
598:hydrogen bonding
507:Bcr-Abl mutation
441:, cytogenic and
215:First generation
48:
45:
39:
27:
26:
19:
2935:
2934:
2930:
2929:
2928:
2926:
2925:
2924:
2900:
2899:
2898:
2875:(10): 918β931.
2862:
2861:
2857:
2848:
2847:
2843:
2834:
2830:
2821:
2817:
2810:
2806:
2775:
2774:
2767:
2726:
2725:
2718:
2708:
2706:
2697:
2696:
2692:
2662:
2661:
2657:
2626:
2625:
2621:
2576:
2575:
2571:
2526:
2525:
2518:
2497:(12): 4701β19.
2487:
2486:
2482:
2451:
2450:
2446:
2401:
2400:
2396:
2389:
2385:
2355:
2354:
2343:
2297:
2296:
2292:
2263:Cancer Research
2256:
2255:
2251:
2207:
2206:
2202:
2172:
2171:
2160:
2124:
2123:
2102:
2064:
2063:
2059:
2013:
2012:
1993:
1957:
1956:
1952:
1908:
1907:
1903:
1894:
1887:
1857:
1856:
1852:
1821:
1820:
1803:
1773:
1772:
1745:
1715:
1714:
1703:
1682:(1β3): 90β100.
1673:
1672:
1668:
1638:
1637:
1628:
1619:
1612:
1603:
1596:
1587:
1583:
1574:
1565:
1556:
1539:
1509:
1508:
1504:
1474:
1473:
1448:
1434:
1433:
1429:
1425:
1416:
1254:Drug screening
1204:
1187:
1175:
1149:
1141:
1117:
1090:
1077:
1056:
980:
956:
943:
896:
891:
882:
862:
818:
805:
796:
776:
752:two dimensional
724:
711:
702:
673:
664:
652:
640:
632:
619:
556:
512:Point mutations
509:
501:adverse effects
491:. That is, the
485:
480:
471:point mutations
426:Drug resistance
423:
421:Drug resistance
354:and side chain
350:-318, the amino
321:activation loop
285:
233:
222:
217:
193:phosphorylation
172:
156:plasma proteins
49:
43:
40:
37:
28:
24:
17:
12:
11:
5:
2933:
2931:
2923:
2922:
2917:
2912:
2902:
2901:
2897:
2896:
2855:
2841:
2828:
2815:
2804:
2765:
2716:
2703:Fierce Biotech
2690:
2671:(6): 980β983.
2655:
2619:
2569:
2540:(5): 401β412.
2516:
2480:
2444:
2394:
2383:
2341:
2310:(2): 281β289.
2290:
2249:
2220:(9): 861β871.
2200:
2181:(2): 129β134.
2158:
2100:
2057:
1991:
1950:
1901:
1885:
1850:
1801:
1743:
1701:
1666:
1647:(2): 288β295.
1626:
1610:
1594:
1581:
1563:
1537:
1502:
1446:
1426:
1424:
1421:
1415:
1412:
1409:
1408:
1405:
1402:
1399:
1396:
1393:
1386:
1379:
1378:
1375:
1372:
1369:
1366:
1363:
1356:
1349:
1348:
1345:
1342:
1339:
1336:
1333:
1326:
1319:
1318:
1315:
1312:
1309:
1306:
1303:
1296:
1289:
1288:
1285:
1282:
1279:
1276:
1273:
1266:
1259:
1258:
1255:
1252:
1249:
1246:
1243:
1236:
1229:
1228:
1225:
1222:
1219:
1216:
1213:
1210:
1203:
1200:
1186:
1183:
1174:
1171:
1148:
1145:
1140:
1137:
1116:
1113:
1089:
1086:
1076:
1073:
1055:
1052:
979:
976:
955:
952:
942:
939:
895:
892:
890:
887:
881:
878:
861:
858:
817:
814:
804:
801:
795:
792:
775:
772:
723:
720:
710:
707:
701:
698:
672:
669:
663:
660:
651:
648:
644:P-glycoprotein
639:
636:
631:
628:
618:
615:
555:
554:T315I mutation
552:
508:
505:
484:
481:
479:
476:
422:
419:
284:
281:
232:
229:
221:
218:
216:
213:
176:chemotherapies
171:
168:
143:that emerged.
121:drugs such as
51:
50:
31:
29:
22:
15:
13:
10:
9:
6:
4:
3:
2:
2932:
2921:
2918:
2916:
2913:
2911:
2908:
2907:
2905:
2892:
2888:
2883:
2878:
2874:
2870:
2866:
2859:
2856:
2851:
2845:
2842:
2839:
2838:
2832:
2829:
2826:
2825:
2819:
2816:
2813:
2808:
2805:
2800:
2796:
2792:
2788:
2784:
2780:
2772:
2770:
2766:
2761:
2757:
2752:
2751:11381/2432276
2747:
2743:
2739:
2735:
2731:
2723:
2721:
2717:
2704:
2700:
2694:
2691:
2686:
2682:
2678:
2674:
2670:
2666:
2659:
2656:
2651:
2647:
2643:
2639:
2635:
2631:
2623:
2620:
2615:
2611:
2607:
2603:
2598:
2593:
2589:
2585:
2581:
2573:
2570:
2565:
2561:
2556:
2551:
2547:
2543:
2539:
2535:
2531:
2523:
2521:
2517:
2512:
2508:
2504:
2500:
2496:
2492:
2484:
2481:
2476:
2472:
2468:
2464:
2460:
2456:
2448:
2445:
2440:
2436:
2432:
2428:
2423:
2418:
2414:
2410:
2406:
2398:
2395:
2392:
2387:
2384:
2379:
2375:
2371:
2367:
2363:
2359:
2352:
2350:
2348:
2346:
2342:
2337:
2333:
2328:
2323:
2318:
2313:
2309:
2305:
2301:
2294:
2291:
2286:
2282:
2277:
2272:
2268:
2264:
2260:
2253:
2250:
2245:
2241:
2236:
2231:
2227:
2223:
2219:
2215:
2211:
2204:
2201:
2196:
2192:
2188:
2184:
2180:
2176:
2169:
2167:
2165:
2163:
2159:
2154:
2150:
2145:
2140:
2137:: vi42βvi46.
2136:
2132:
2128:
2121:
2119:
2117:
2115:
2113:
2111:
2109:
2107:
2105:
2101:
2096:
2092:
2088:
2084:
2080:
2076:
2072:
2068:
2061:
2058:
2053:
2049:
2044:
2039:
2034:
2029:
2025:
2021:
2020:Core Evidence
2017:
2010:
2008:
2006:
2004:
2002:
2000:
1998:
1996:
1992:
1987:
1983:
1978:
1973:
1969:
1965:
1961:
1954:
1951:
1946:
1942:
1938:
1934:
1929:
1924:
1920:
1916:
1912:
1905:
1902:
1898:
1892:
1890:
1886:
1881:
1877:
1873:
1869:
1866:(3): 1070β9.
1865:
1861:
1854:
1851:
1846:
1842:
1838:
1834:
1830:
1826:
1818:
1816:
1814:
1812:
1810:
1808:
1806:
1802:
1797:
1793:
1789:
1785:
1782:(1β2): 3β13.
1781:
1777:
1770:
1768:
1766:
1764:
1762:
1760:
1758:
1756:
1754:
1752:
1750:
1748:
1744:
1739:
1735:
1731:
1727:
1723:
1719:
1712:
1710:
1708:
1706:
1702:
1697:
1693:
1689:
1685:
1681:
1677:
1670:
1667:
1662:
1658:
1654:
1650:
1646:
1642:
1635:
1633:
1631:
1627:
1623:
1617:
1615:
1611:
1607:
1601:
1599:
1595:
1591:
1585:
1582:
1578:
1572:
1570:
1568:
1564:
1560:
1554:
1552:
1550:
1548:
1546:
1544:
1542:
1538:
1533:
1529:
1525:
1521:
1517:
1513:
1506:
1503:
1498:
1494:
1490:
1486:
1482:
1478:
1471:
1469:
1467:
1465:
1463:
1461:
1459:
1457:
1455:
1453:
1451:
1447:
1442:
1438:
1431:
1428:
1422:
1420:
1413:
1406:
1403:
1400:
1397:
1394:
1391:
1387:
1384:
1381:
1380:
1376:
1373:
1370:
1367:
1364:
1361:
1357:
1354:
1351:
1350:
1346:
1343:
1340:
1337:
1334:
1331:
1327:
1324:
1321:
1320:
1316:
1313:
1310:
1307:
1304:
1301:
1297:
1295:(BMS-345825)
1294:
1291:
1290:
1286:
1283:
1280:
1277:
1274:
1271:
1267:
1264:
1261:
1260:
1256:
1253:
1250:
1247:
1244:
1241:
1237:
1234:
1231:
1230:
1226:
1223:
1220:
1217:
1214:
1211:
1208:
1207:
1201:
1199:
1197:
1193:
1191:
1184:
1182:
1180:
1172:
1170:
1167:
1162:
1153:
1146:
1144:
1138:
1136:
1133:
1129:
1121:
1114:
1112:
1109:
1104:
1100:
1096:
1087:
1085:
1082:
1074:
1072:
1068:
1065:
1061:
1053:
1047:
1043:
1041:
1037:
1032:
1027:
1023:
1019:
1015:
1011:
1006:
1003:
998:
994:
984:
977:
975:
972:
966:
964:
960:
953:
951:
949:
940:
938:
936:
932:
928:
924:
920:
916:
912:
908:
900:
893:
888:
886:
879:
877:
875:
874:aminothiazole
871:
866:
859:
854:
850:
846:
841:
837:
834:
830:
829:hydrochloride
826:
822:
815:
809:
802:
800:
793:
791:
789:
785:
781:
773:
768:
763:
759:
757:
753:
748:
744:
740:
739:proliferation
735:
733:
728:
721:
715:
708:
706:
699:
697:
695:
691:
687:
683:
678:
670:
668:
661:
659:
657:
649:
647:
645:
637:
635:
629:
627:
624:
616:
614:
612:
609:(Iclusig) by
608:
603:
599:
595:
591:
589:
584:
582:
577:
573:
569:
565:
561:
553:
551:
549:
545:
541:
537:
533:
529:
525:
524:chronic phase
521:
516:
513:
506:
504:
502:
498:
494:
490:
482:
477:
475:
472:
468:
467:amplification
459:
455:
453:
449:
448:retrospective
444:
440:
435:
431:
427:
420:
418:
417:to imatinib.
416:
411:
409:
405:
401:
397:
393:
389:
388:van der Waals
385:
381:
377:
373:
369:
365:
361:
357:
353:
349:
345:
341:
337:
333:
332:hydrogen bond
328:
326:
322:
318:
315:
310:
306:
302:
298:
289:
282:
280:
278:
274:
270:
266:
262:
261:lead compound
258:
254:
250:
246:
237:
230:
228:
226:
219:
214:
212:
210:
206:
200:
198:
194:
190:
185:
181:
177:
169:
167:
163:
161:
157:
153:
149:
144:
142:
138:
137:
132:
128:
124:
120:
116:
112:
107:
105:
101:
97:
93:
92:chromosome 22
89:
85:
81:
77:
73:
69:
65:
61:
57:
47:
35:
30:
21:
20:
2872:
2868:
2858:
2844:
2836:
2831:
2823:
2818:
2807:
2782:
2778:
2733:
2729:
2707:. Retrieved
2702:
2693:
2668:
2664:
2658:
2633:
2629:
2622:
2587:
2583:
2572:
2537:
2533:
2494:
2490:
2483:
2458:
2454:
2447:
2412:
2408:
2397:
2386:
2361:
2357:
2307:
2303:
2293:
2266:
2262:
2252:
2217:
2213:
2203:
2178:
2174:
2134:
2130:
2070:
2066:
2060:
2023:
2019:
1967:
1963:
1953:
1918:
1914:
1904:
1896:
1863:
1859:
1853:
1828:
1824:
1779:
1775:
1721:
1717:
1679:
1675:
1669:
1644:
1640:
1621:
1605:
1589:
1584:
1576:
1558:
1515:
1505:
1480:
1476:
1440:
1436:
1430:
1417:
1194:
1189:
1188:
1176:
1158:
1142:
1134:
1130:
1126:
1091:
1078:
1069:
1057:
1007:
989:
967:
957:
944:
923:solubilizing
919:carbonitrile
905:
883:
872:groups. The
867:
863:
819:
797:
777:
736:
725:
703:
674:
665:
653:
641:
633:
620:
587:
580:
570:(C -> T)
557:
517:
510:
497:DNA sequence
486:
464:
424:
412:
329:
324:
294:
242:
223:
201:
199:cell death.
189:human genome
180:intervention
173:
164:
145:
134:
108:
104:pathogenesis
84:chromosome 9
76:Peter Nowell
59:
55:
54:
44:January 2017
41:
33:
2534:Cancer Cell
2026:: 207β213.
1590:Cancer Cell
1385:(INNO-406)
1355:(AP-24534)
1147:Development
1108:hydrophilic
1088:Development
1026:Sonogashira
1002:cyclopropyl
997:cyclopentyl
978:Development
915:quinazoline
894:Development
870:carboxamide
816:Development
747:Synergistic
722:Development
528:blast phase
439:hematologic
415:intolerance
408:piperazinyl
392:hydrophobic
364:carboxylate
295:Since then
231:Development
184:fusion gene
127:hydroxyurea
2904:Categories
2812:Rebastinib
2073:: 106115.
1899:: 804-820.
1624:: 101-108.
1592:: 117-123.
1579:: S19-S27.
1561:: 461-476.
1559:Hematology
1423:References
1325:(SKI-606)
1224:Discovery
1212:Structure
1190:Rebastinib
1060:pyridazine
941:Resistance
880:Resistance
794:Resistance
780:lipophilic
686:hypothesis
544:C-terminal
540:SH2 domain
452:compliance
434:cell lines
396:amino acid
376:piperazine
352:pyrimidine
257:Pyrimidine
141:resistance
131:interferon
90:) gene at
62:) are the
2095:258446069
1532:0362-5664
1401:Inactive
1383:Bafetinib
1371:Inactive
1353:Ponatinib
1341:Inactive
1323:Bosutinib
1293:Dasatinib
1281:Inactive
1265:(AMN107)
1263:Nilotinib
1251:Inactive
1235:(STI571)
1196:Asciminib
1166:thiophene
1081:Bafetinib
1040:ponatinib
1018:acetylene
993:arylamide
991:with a di
963:ponatinib
911:quinoline
907:Bosutinib
902:Bosutinib
853:dasatinib
821:Dasatinib
767:nilotinib
727:Nilotinib
671:Solutions
607:Ponatinib
590:soleucine
572:base pair
560:ponatinib
443:molecular
382:-360 and
265:imidazole
245:structure
197:apoptotic
119:cytotoxic
2910:Leukemia
2891:20597967
2799:18621522
2760:18078752
2685:18191450
2650:17376680
2614:15211440
2606:16105974
2564:19878872
2511:20513156
2475:19572547
2431:15256422
2378:20399641
2336:19536317
2285:16740718
2244:20387067
2195:19783301
2153:17591830
2087:37137346
2052:20694077
1986:15315971
1937:11423618
1880:10910924
1845:20817538
1796:16172030
1738:16332440
1696:19835861
1661:19217274
1497:20537386
1233:Imatinib
1215:H-bonds
1022:2-butyne
933:vs. 3,5
845:PDB 2GQG
694:pathways
583:hreonine
564:cytosine
437:meeting
432:derived
430:in vitro
356:hydroxyl
344:backbone
340:pyridine
336:imatinib
269:activity
253:Novartis
225:Imatinib
123:busulfan
115:imatinib
96:oncogene
2555:2804470
2439:6853673
2327:2697539
2235:2908401
2043:2899790
1945:1279564
1915:Science
1622:Targets
1443:: 1497.
1437:Science
1311:Active
1202:Summary
1179:methoxy
1173:Binding
1115:Binding
1064:ethynyl
1054:Binding
1010:Docking
860:Binding
788:anilino
784:pyridyl
774:Binding
756:spatial
682:potency
568:thymine
526:to the
346:-NH of
342:-N and
283:Binding
277:potency
170:History
100:Bcr-Abl
34:updated
2889:
2797:
2758:
2709:17 May
2683:
2648:
2612:
2604:
2562:
2552:
2509:
2473:
2437:
2429:
2376:
2334:
2324:
2283:
2242:
2232:
2193:
2151:
2093:
2085:
2050:
2040:
1984:
1943:
1935:
1878:
1843:
1794:
1736:
1694:
1659:
1608:: 3-7.
1530:
1495:
1185:Others
1103:chloro
1095:fluoro
971:purine
855:(red).
732:potent
690:clones
623:P-loop
594:oxygen
548:P-loop
532:P-loop
325:DFGout
301:domain
152:domain
2610:S2CID
2584:Blood
2435:S2CID
2409:Blood
2091:S2CID
1964:Blood
1941:S2CID
1860:Blood
1209:Drug
1099:bromo
1014:vinyl
847:) of
823:is a
769:(red)
611:Ariad
576:codon
536:helix
446:that
273:ortho
2887:PMID
2795:PMID
2756:PMID
2711:2022
2681:PMID
2646:PMID
2602:PMID
2560:PMID
2507:PMID
2471:PMID
2427:PMID
2374:PMID
2332:PMID
2281:PMID
2240:PMID
2191:PMID
2149:PMID
2083:PMID
2048:PMID
1982:PMID
1933:PMID
1876:PMID
1841:PMID
1792:PMID
1780:1754
1734:PMID
1692:PMID
1657:PMID
1528:ISSN
1493:PMID
1101:and
929:1,4
927:IC50
656:OCT1
493:gene
136:Time
2877:doi
2787:doi
2746:hdl
2738:doi
2673:doi
2638:doi
2592:doi
2588:106
2550:PMC
2542:doi
2499:doi
2463:doi
2417:doi
2413:104
2366:doi
2322:PMC
2312:doi
2271:doi
2230:PMC
2222:doi
2183:doi
2139:doi
2075:doi
2071:180
2038:PMC
2028:doi
1972:doi
1968:104
1923:doi
1919:293
1868:doi
1833:doi
1784:doi
1726:doi
1684:doi
1680:625
1649:doi
1520:doi
1485:doi
1441:132
743:Tyr
677:CML
566:to
520:CML
404:Val
400:Leu
384:His
380:Ile
372:Asp
368:Glu
366:of
360:Thr
358:of
348:Met
317:Gly
314:Phe
312:Asp
309:ATP
129:or
88:Bcr
80:Abl
60:TKI
2906::
2885:.
2873:40
2871:.
2867:.
2793:.
2783:18
2781:.
2768:^
2754:.
2744:.
2734:18
2732:.
2719:^
2701:.
2679:.
2669:32
2667:.
2644:.
2634:17
2632:.
2608:.
2600:.
2586:.
2582:.
2558:.
2548:.
2538:16
2536:.
2532:.
2519:^
2505:.
2495:53
2493:.
2469:.
2459:52
2457:.
2433:.
2425:.
2411:.
2407:.
2372:.
2362:46
2360:.
2344:^
2330:.
2320:.
2306:.
2302:.
2279:.
2267:66
2265:.
2261:.
2238:.
2228:.
2218:89
2216:.
2212:.
2189:.
2179:34
2177:.
2161:^
2147:.
2135:18
2133:.
2129:.
2103:^
2089:.
2081:.
2069:.
2046:.
2036:.
2022:.
2018:.
1994:^
1980:.
1966:.
1962:.
1939:.
1931:.
1917:.
1913:.
1888:^
1874:.
1864:96
1862:.
1839:.
1829:18
1827:.
1804:^
1790:.
1778:.
1746:^
1732:.
1722:16
1720:.
1704:^
1690:.
1678:.
1655:.
1645:21
1643:.
1629:^
1613:^
1597:^
1566:^
1540:^
1526:.
1514:.
1491:.
1481:34
1479:.
1449:^
1439:.
1395:6
1365:5
1338:-
1335:-
1305:3
1275:4
1245:6
1097:,
1042:.
935:nM
931:nM
538:,
327:.
279:.
162:.
125:,
2893:.
2879::
2852:.
2801:.
2789::
2762:.
2748::
2740::
2713:.
2687:.
2675::
2652:.
2640::
2616:.
2594::
2566:.
2544::
2513:.
2501::
2477:.
2465::
2441:.
2419::
2380:.
2368::
2338:.
2314::
2308:5
2287:.
2273::
2246:.
2224::
2197:.
2185::
2155:.
2141::
2097:.
2077::
2054:.
2030::
2024:4
1988:.
1974::
1947:.
1925::
1882:.
1870::
1847:.
1835::
1798:.
1786::
1740:.
1728::
1698:.
1686::
1663:.
1651::
1534:.
1522::
1499:.
1487::
588:I
581:T
98:(
58:(
46:)
42:(
36:.
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