Characterization of a Conserved Structural Determinant Controlling Protein Kinase Sensitivity to Selective Inhibitors

Blencke, Stephanie; Zech, Birgit; Engkvist, Ola; Greff, Zoltán; Őrfi, László; Horváth, Zoltán; Kéri, Gÿorgý; Ullrich, Axel; Daub, Henrik

doi:10.1016/j.chembiol.2004.02.029

Cited by 138 publications

(118 citation statements)

References 33 publications

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“…The mutation status of patients has, to our knowledge, not been reported, and our results suggest that patients with gatekeeper mutations in KIT may be among those treated successfully with SU-11248 for imatinibresistant GIST. The recent description of T790M as a secondary clinical gefitiniband erlotinib-resistance mutation in EGFR was anticipated by in vitro studies with gefitinib in the context of wild-type EGFR (18). The finding that EGFR inhibitors already in clinical trials can inhibit EGFR(L858R͞T790M) suggests that refractory or relapsed patients with the T790M mutation may benefit from treatment with EKB-569 or CI-1033.…”

Section: Discussionmentioning

confidence: 99%

“…This threonine residue, also called the gatekeeper, is known to be an important determinant of inhibitor binding in the context of multiple kinases (13,18,42,43). Imatinib-resistant mutations at other positions in the ABL kinase tend to weaken binding only moderately, albeit enough to confer clinical resistance.…”

Section: Discussionmentioning

confidence: 99%

“…and C.L.S., unpublished observations). It has been shown that the Hsp90 inhibitors geldanamycin and 17-allylaminogeldanamycin can induce degradation of BCR-ABL(T315I) (44), but the only direct inhibitor of BCR-ABL(T315I) described so far is a non-ATPcompetitive preclinical compound (45 Although it has been observed that compounds chemically related to SU-11248 can inhibit kinases with mutations at the conserved threonine residue (18), our finding that SU-11248 inhibits KIT(V559D͞T670I) with no apparent loss in potency has, to our knowledge, not been described previously, and is of direct clinical relevance because SU-11248 is in late stage trials for imatinib-resistant GIST. It has been reported recently that the trials will be halted ahead of schedule because of the apparent efficacy of the compound (Pharmaprojects database).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, some of the common drug-resistant mutations in these kinases are structurally related: BCR-ABL(T315I), KIT(T670I), and EGFR(T790M) contain homologous mutations of the conserved ''gatekeeper'' threonine residue (7,10,11). Mutations of this residue can have profound effects on small molecule binding in the context of different kinases (13,18), yet the mutations do not inactivate kinase function. Based on the behavior of imatinib, BMS-354825 (also known as dasatinib) (19) and other ABL inhibitors (20)(21)(22), all of which share a significant loss of affinity for ABL(T315I) relative to other ABL variants, one might conclude that it is particularly difficult to inhibit ABL(T315I) with an ATP-competitive compound.…”

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confidence: 99%

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Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

Carter

Wodicka

Shah

et al. 2005

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

521

390

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To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotinib. The mutations weaken or prevent drug binding, and interestingly, one of the most common sites of mutation in all three kinases is a highly conserved ''gatekeeper'' threonine residue near the kinase active site. We have identified existing clinical compounds that bind and inhibit drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the Aurora kinase inhibitor VX-680 and the p38 inhibitor BIRB-796 inhibit the imatinib-and BMS-354825-resistant ABL(T315I) kinase. The KIT͞FLT3 inhibitor SU-11248 potently inhibits the imatinib-resistant KIT(V559D͞T670I) kinase, consistent with the clinical efficacy of SU-11248 against imatinib-resistant gastrointestinal tumors, and the EGFR inhibitors EKB-569 and CI-1033, but not GW-572016 and ZD-6474, potently inhibit the gefitiniband erlotinib-resistant EGFR(L858R͞T790M) kinase. EKB-569 and CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of gefitinib͞ erlotinib-resistant non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find compounds that may serve as starting points for the development of nextgeneration drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy. drug resistance ͉ gatekeeper mutation ͉ kinase inhibitor

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

Carter

Wodicka

Shah

et al. 2005

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

521

390

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“…T315 serves as a gatekeeper residue that controls access to a hydrophobic region of the enzymatic active site that is not contacted by ATP (1,9). Mutation at this critical residue confers resistance to almost all ATP-competitive inhibitors of the ABL kinase (22,(25)(26)(27)(28)(29)(30)(31)(32). A comparable substitution in platelet-derived growth factor receptor (PDGFR) ␣ and PDGFR␤ can be inhibited by PKC412 and SU6668, respectively, compounds that avoid contact with the hydrophobic region (31,33).…”

Section: Discussionmentioning

confidence: 99%

Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance

Azam

Nardi

Shakespeare

et al. 2006

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

102

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Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukemia. Many mutations favor active kinase conformations that preclude imatinib binding. Because the active forms of ABL and SRC resemble one another, we tested two dual SRC-ABL kinase inhibitors, AP23464 and PD166326, against 58 imatinib-resistant (IM R ) BCR͞ABL kinase variants. Both compounds potently inhibit most IM R variants, and in vitro drug selection demonstrates that active (AP23464) and open (PD166326) conformation-specific compounds are less susceptible to resistance than imatinib. Combinations of inhibitors suppressed essentially all resistance mutations, with the notable exception of T315I. Guided by mutagenesis studies and molecular modeling, we designed a series of AP23464 analogues to target T315I. The analogue AP23846 inhibited both native and T315I variants of BCR͞ABL with submicromolar potency but showed nonspecific cellular toxicity. Our data illustrate how conformational dynamics of the ABL kinase accounts for the activity of dual SRC-ABL inhibitors against IM R -mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance.kinase inhibitors ͉ imatinib ͉ combination chemotherapy ͉ chronic myelogenous leukemia T he small molecule protein kinase inhibitors imatinib (1-5), gefitinib (6), and erlotinib (7, 8) are susceptible to resistance in patients because of amino acid substitutions in the target protein.Imatinib inhibits BCR͞ABL by stabilizing the kinase in a catalytically inactive conformation (9). Point mutations in the ABL kinase domain can thwart drug binding by direct steric hindrance or by destabilizing the inactive kinase conformation that is required for imatinib binding (2, 3). Consequently, developing drugs that target the open or active conformation of the kinase may prove effective in rescuing patients who develop imatinib resistance.Previously, we carried out an in vitro screen for imatinib resistance and identified a large number of mutant amino acid residues outside the active site that did not appear to act by direct steric hindrance of drug binding. Several of these residues were homologous to SRC residues known to play critical roles in maintaining an assembled, autoinhibited SRC kinase conformation (10-13), and some previously had been implicated by site-directed mutagenesis in ABL kinase regulation (14,15). We reasoned that these conformational, or allosteric, mutants exerted effects on drug binding by favoring adoption of the active kinase conformation. Using inferences from the mutagenesis studies, we proposed a model for the assembled ABL kinase that closely resembled the autoinhibited SRC structure (3). Crystallographic and biochemical data published alongside our mutagenesis report confirmed that ABL indeed was regulated in a SRC-like manner (16)(17)(18).The striking similarity between the catalytically active states of the SRC and ABL kinases prompted us to investigate whether SRC kinase inhibitors might...

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Protein Kinase Inhibitors in Drug Discovery

Parang

Sun

2010

Pharmaceutical Sciences Encyclopedia

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Protein kinases (PKs) have essential roles in cell‐signaling pathways by interacting with extracellular ligands such as growth factors and hormones and transmitting signals across the cell membrane to the cytoplasm and the nucleus. It is important to understand the mechanistic features of the particular target kinase when designing protein kinase inhibitors (PKIs). This chapter focuses on inhibitors directed against critical molecular targets that are approved or are in clinical trials.

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Characterization of a Conserved Structural Determinant Controlling Protein Kinase Sensitivity to Selective Inhibitors

Cited by 138 publications

References 33 publications

Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance

Protein Kinase Inhibitors in Drug Discovery

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