New insights into small‐molecule inhibitors of Bcr‐Abl

Abstract

Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a defined genetic abnormality, the Bcr-Abl fusion gene on the Philadelphia chromosome that expresses the constitutively activated tyrosine kinase (TK) Bcr-Abl. This enzyme leads to the malignant transformation of primitive hematopoietic cells and to the consequent disease. The central role of Bcr-Abl in the pathogenesis of CML culminated in the discovery of imatinib (an ATP-competitive inhibitor), which is currently the frontline therapy for CML. Unfortunately, the initial enthusiasm generated by its high response rate has been dampened by the development of resistance, especially in the advanced phases of CML. To overcome imatinib resistance, several second-generation ATP-competitive inhibitors endowed with increased potency against imatinib-resistant mutants have been developed: the dual Src/Abl inhibitor dasatinib and the Abl inhibitor nilotinib have been recently approved by US-FDA for the treatment of imatinib-resistant CML, and many other compounds are currently in clinical trial. Although second-generation TK inhibitors have shown to be clinically effective against most of the imatinib-resistant mutants, to date poor results have been obtained in the treatment of the Bcr-Abl T315I mutant. In this review we will report the most interesting second-generation Abl and dual Src/Abl inhibitors recently entered in clinical trial, but also the new ATP-competitive and uncompetitive inhibitors published in the last few years, focusing on their chemical structure, mechanism of action, and structure-activity relationship.

4-Nerolidylcatechol analogues as promising anticancer agents

“…However, resistance to imatinib drove to development of the second and third tyrosine kinase inhibitors (Ren, 2005;Tanaka and Kimura, 2008). Thus, alternative drugs have been developed to circumvent this resistance (De Martino et al 2011;Lamontanara et al 2013;Schenone et al 2011). In this respect, the compounds (1), (3) and (5) induced a significant accumulation of cell population in sub-G1 phase suggesting that these compounds were able to promote apoptosis in K562 cells, a multiple drug resistance cell line.…”

Dual Src and Abl inhibitors target wild type Abl and the AblT315I Imatinib-resistant mutant with different mechanisms

“…3,16,17 This mutant is not effectively targeted by any of the second-generation Imatinib derivatives, such as dasatinib, nilotinib, bosutinib and INNO-406. 7,18 Mass spectrometry analysis has revealed that, contrary to other mutations such as Y253H and E255V, the T315I substitution induces conformational changes in the Abl structure, particularly in the active site region (aminoacids 287-302) and in the SH3 linker domain.…”

Bcr-Abl tyrosine kinase inhibitors: a patent review

“…A reciprocal translocation fuses the Abl gene on chromosome 9 with the breakpoint cluster region (Bcr) gene on chromosome 22. This fusion forms the Philadelphia (Ph) chromosome that generates a fusion protein, Bcr Abelson TK (Bcr-Abl), which possesses the TK activity of Abl and is constitutively active.…”