The Crystal Structure of Abl Kinase with BMS-354825, a Dual SRC/ABL Kinase Inhibitor.

Abstract

Chronic myeloid leukemia (CML) is a stem cell disorder caused by a constitutively activated tyrosine kinase, the BCR-ABL oncoprotein. Imatinib (STI571, Gleevec) is a small-molecule inhibitor of this kinase that produces clinical remissions in CML patients and is now frontline therapy for this disease. While this agent has a high rate of clinical success in early phases of CML, development of resistance to this drug becomes increasingly problematic in later stages of the disease. BMS-354825, a small-molecule dual-function SRC/ABL tyrosine kinase inhibitor, appears to overcome many of the limitations associated with imatinib therapy. BMS-354825 is 500-fold more potent than imatinib against BCR-ABL and more importantly retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants (Shah et al., Science, 2004;305(5682):399). In addition, BMS-354825 proved to be equally effective against several pre-clinically and clinically derived tumor models of imatinib resistance (Lee et al., Proceedings of the AACR, Volume 45, March 2004 abstract number 3937). In order to better understand the molecular basis of the relationship between inhibitor chemistry and biological activity, the three-dimensional structure of the kinase domain of Abl kinase complexed with BMS-354825 was determined by X-ray crystallography. The structure reveals that BMS-354825 binds in the ATP-binding site. A comparison with the imatinib-Abl complex (PDB entry 1IEP) reveals that the central cores of BMS-354825 and imatinib occupy overlapping regions but that these two inhibitors extend in opposite directions. The activation loop is observed to be in the active conformation in the presence of bound BMS-354825 in contrast to bound imatinib. There do not appear to be any steric clashes that would preclude BMS-354825 from also binding to the inactive conformation of the activation loop. This observation suggests that the increased binding affinity of BMS-354825 over imatinib is at least partially due to its apparent ability to recognize multiple states of the enzyme. The P-loop is partially disordered as indicated by high B-factors and broken electron density which suggests that interactions between this part of the protein and BMS-354825 are less critical for binding. Interestingly, several imatinib-resistant mutations occur in the P-loop. The structure was analyzed for the 15 imatinib-resistant BCR-ABL mutants and attempts are made to rationalize the activity of BMS-354825 against these mutants.

Strategies for senolytic drug discovery

“…Kinases regulate a broad range of cellular processes relevant to senescence including cell cycle arrest, pro‐inflammatory signaling, nutrient signaling, and the DNA damage response (Anerillas et al, 2020 ; Gaestel et al, 2009 ; Lu & Hunter, 2018 ). The early senolytic dasatinib, is an inhibitor of various Abl, Tec, and Src family kinases (Das et al, 2006 ; Hantschel et al, 2007 ; Tokarski et al, 2004 ). Additional senolytics were identified by screening the Selleck Chem L1200 kinase inhibitor library (Cho et al, 2020 ).…”

Cumulative clinical experience from a decade of use: imatinib as first-line treatment of chronic myeloid leukemia

“…In addition, dasatinib binds to ABL through fewer interactions than imatinib and nilotinib, and its affinity for binding to ABL is higher than that of imatinib. 88 , 96 Dasatinib was reported to have antiproliferative effects on all CML cells bearing imatinib-resistant BCR-ABL mutants except for those bearing the T315I mutation. 97 Phase I and phase II studies revealed that the adverse effects of dasatinib, such as headache, rash, diarrhea, and edema, were fewer than those of imatinib.…”

Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia—Is There an Optimal Treatment Plan?

“…It can bind the ABL kinase in both the inactive and the active conformation 26,27 and has a 325-fold greater binding than imatinib against unmutated bcr-abl in vitro. 26 The SRC/ABL Tyrosine kinase inhibition Activity: Research Trials of dasatinib (START) program has evaluated dasatinib (70mg twice daily [BID]) in patients with imatinibresistant or -intolerant Ph + CML.…”