Inhibitors of the Abl kinase directed at either the ATP- or myristate-binding site

Fabbro, Doriano; Manley, Paul W.; Jahnke, Wolfgang; Liebetanz, Janis; Szyttenholm, Alexandra; Fendrich, Gabriele; Strauss, André; Zhang, Jianming; Gray, Nathanael S.; Adrián, Francisco; Warmuth, Markus; Pellé, Xavier; Grotzfeld, Robert M.; Berst, Frédéric; Marzinzik, Andreas L.; Cowan‐Jacob, Sandra W.; Furet, Pascal; Mestan, Jürgen

doi:10.1016/j.bbapap.2009.12.009

Cited by 61 publications

(65 citation statements)

References 40 publications

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“…Notably, our in silico methodology (28) ranked the affinity of the different BCR-ABL1 isoforms similarly to available experimental data obtained in biochemical assays with imatinib, dasatinib, and nilotinib (SI Appendix, Figs. S3-S5) (6,19,20,(29)(30)(31), thus validating the adopted computational approach and supporting its use to discern differences in the mechanisms of resistance to specific TKIs among distinct mutants (SI Appendix, Tables S4-S8).…”

Section: In Silico Modeling Of Polymutants In Complex With Imatinib Andmentioning

confidence: 53%

Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy

Gibbons

Pricl

Posocco

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The acquisition of mutations within the BCR-ABL1 kinase domain is frequently associated with tyrosine kinase inhibitor (TKI) failure in chronic myeloid leukemia. Sensitive sequencing techniques have revealed a high prevalence of compound BCR-ABL1 mutations (polymutants) in patients failing TKI therapy. To investigate the molecular consequences of such complex mutant proteins with regards to TKI resistance, we determined by cloning techniques the presence of polymutants in a cohort of chronic-phase patients receiving imatinib followed by dasatinib therapy. The analysis revealed a high frequency of polymutant BCR-ABL1 alleles even after failure of frontline imatinib, and also the progressive exhaustion of the pool of unmutated BCR-ABL1 alleles over the course of sequential TKI therapy. Molecular dynamics analyses of the most frequent polymutants in complex with TKIs revealed the basis of TKI resistance. Modeling of BCR-ABL1 in complex with the potent pan-BCR-ABL1 TKI ponatinib highlighted potentially effective therapeutic strategies for patients carrying these recalcitrant and complex BCR-ABL1 mutant proteins while unveiling unique mechanisms of escape to ponatinib therapy. compound mutation | ponatinib resistance

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Section: In Silico Modeling Of Polymutants In Complex With Imatinib Andmentioning

confidence: 53%

Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy

Gibbons

Pricl

Posocco

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, it is urgent to To achieve this goal, some small molecule compounds have been designed to target Bcr-Abl motifs remote from the kinase domain. The activity of these drugs remains unaffected by the presence of mutations in the kinase domain of the enzyme, including ON012380, GNF-2, and GNF-5 [13,14,[28][29][30][31] . GNF-5, an analog of GNF-2 having improved pharmacokinetic properties, when combined with the ATP-competitive inhibitors imatinib or, can suppressed the emergence of resistance mutations in vitro, displayed inhibitory activity against T315I Bcr-Abl and displayed in vivo efficacy against the recalcitrant T315I Bcr-Abl mutant in a murine bone-marrow transplantation model.…”

Section: Discussionmentioning

confidence: 99%

Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro

Wāng

Chen

et al. 2014

Acta Pharmacol Sin

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Aim: To find new kinase inhibitors that overcome the imatinib resistance in treatment of chronic myeloid leukemia (CML), we synthesized C817, a novel derivative of curcumin, and tested its activities against wild-type (WT) and imatinib-resistant mutant Abl kinases, as well as in imatinib-sensitive and resistant CML cells in vitro. Methods: 32D cells harboring WT or mutant Abl kinases (nucleotide binding P-loop mutants Q252H, Y253F, and imatinib contact residue mutant T315I), as well as K562/G01 cells (with whole Bcr-Abl gene amplication) were tested. Kinase activity was measured using Kinase-Glo Luminescent Kinase Assay Platform in recombinant WT and mutant (Q252H, Y253F, and T315I) Abl kinases. Cell proliferation and apoptosis were examined using MTT assay and flow cytometry, respectively. The phosphorylation levels of Bcr-Abl initiated signaling proteins were analyzed using Western blotting. Colony forming units (CFU) growth and long term culture-initiating cells (LTC-ICs) were used to test the effects of C817 on human leukemia progenitor/stem cells. Results: C817 potently inhibited both WT and mutant (Q252H, Y253F, and T315I) Abl kinase activities in a non-ATP competitive manner with the values of IC 50 at low nanomole levels. In consistent with above results, C817 suppressed the growth of both imatinib-sensitive and resistant CML cells, including wild-type K562, K562/G01, 32D-T315I, 32D-Q252H, and 32D-Y253F cells with the values of IC 50 at low micromole levels. C817 (0.5 or 1 μmol/L) dose-dependently inhibited the phosphorylation of Bcr-Abl and downstream proteins STAT-5 and CrkL in imatinib-resistant K562/G01 cells. Furthermore, C817 significantly suppressed CFU growth and LTC-ICs, implicating that C817 could eradiate human leukemia progenitor/stem cells. Conclusion: C817 is a promising compound for treatment of CML patients with Bcr-Abl kinase domain mutations that confer imatinib resistance.

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“…Type 3 inhibitors that are further away from the ATP site are the myristate (myr) pocket binders located in the bottom of the C-lobe of ABL (Adrian et al, 2006;Zhang et al, 2009;Fabbro et al, 2010), CHK1 inhibitors that occupy, in part, the substrate-binding site (Converso et al, 2009), and JNK1 inhibitors that occupy the mitogen-activated protein kinase insert region and A-loop (Comess et al, 2011), to only cite a few. A more comprehensive review on type 3 inhibitors has at ASPET Journals on May 9, 2018 molpharm.aspetjournals.org…”

Section: Reversible (Noncovalent) Inhibitorsmentioning

confidence: 99%

25 Years of Small Molecular Weight Kinase Inhibitors: Potentials and Limitations

2014

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Deregulation of protein and lipid kinase activities leads to a variety of pathologies, ranging from cancer inflammatory diseases, diabetes, infectious diseases, and cardiovascular disorders. Protein kinases and lipid kinases represent, therefore, an important target for the pharmaceutical industry. In fact, approximately one-third of all protein targets under investigation in the pharmaceutical industry are protein or lipid kinases. To date, 30 kinase inhibitors have been approved, which, with few exceptions, are mainly for oncological indications and directed against only a handful of protein and lipid kinases, leaving 70% of the kinome untapped. Despite these successes in kinase drug discovery, the development of kinase inhibitors with outstanding selectivity, identification and validation of driver kinase(s) in diseases, and the emerging problem of resistance to the inhibition of key target kinases remain major challenges. This minireview provides an insight into protein and lipid kinase drug discovery with respect to achievements, binding modes of inhibitors, and novel avenues for the generation of second-generation kinase inhibitors to treat cancers.

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Inhibitors of the Abl kinase directed at either the ATP- or myristate-binding site

Cited by 61 publications

References 40 publications

Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy

Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy

Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro

25 Years of Small Molecular Weight Kinase Inhibitors: Potentials and Limitations

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