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

Mohammad Azam, Valentina Nardi, William C. Shakespeare, Chester A. Metcalf, Regine S. Bohacek, Yihan Wang, Raji Sundaramoorthi, Piotr Sliz, Darren R. Veach, William G. Bornmann, Bayard Clarkson, David C. Dalgarno, Tomi K. Sawyer, George Q. Daley

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

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 (IMR) BCR/ABL kinase variants. Both compounds potently inhibit most IMR 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 BCR/ABL 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 IMR-mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance.

Original languageEnglish
Pages (from-to)9244-9249
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number24
DOIs
StatePublished - 13 Jun 2006
Externally publishedYes

Keywords

  • Chronic myelogenous leukemia
  • Combination chemotherapy
  • Imatinib
  • Kinase inhibitors

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