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Updated: Apr 20, 2026
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Discovery of allosteric BCR-ABL inhibitors from phenotypic screen to clinical candidate
Nathanael S Gray1, Doriano Fabbro2
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston MA, USA.
Abstract:
The development of imatinib, an ATP-competitive inhibitor of the BCR-ABL oncoprotein, has revolutionized the treatment of chronic myelogenous leukemia (CML). Unfortunately, the leukemia eventually becomes resistant imatinib as a result of emergence of cells expressing drug insensitive BCR-ABL mutant proteins. This has motivated the development of several next-generation ATP-competitive drugs. This chapter describes the discovery and development of a complementary strategy involving inhibiting BCR-ABL by targeting an allosteric binding site. Compounds that bind to the myristate-binding pocket of BCR-ABL are able to induce formation of an "inactive" state and are able to overcome resistance mutations located in the ATP-binding pocket including the recalcitrant T315I "gatekeeper" mutation. Myristate-pocket inhibitors are also able to function synergistically with ATP-competitive inhibitors in cellular and murine models of CML and this dual inhibitory strategy is currently being investigated in the clinic.
Insights
Targeting the myristate-binding pocket of BCR-ABL offers a new strategy to overcome imatinib resistance in chronic myelogenous leukemia (CML). This approach inhibits an inactive state, effectively combating mutations like T315I.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Imatinib revolutionized chronic myelogenous leukemia (CML) treatment by inhibiting the BCR-ABL oncoprotein.
- Leukemia cells develop resistance to imatinib due to BCR-ABL mutations.
- Next-generation ATP-competitive drugs have been developed, but resistance remains a challenge.
Purpose of the Study:
- To describe the discovery and development of a complementary strategy to inhibit BCR-ABL.
- To investigate targeting an allosteric binding site, specifically the myristate-binding pocket, of BCR-ABL.
- To overcome imatinib resistance, including the T315I mutation.
Main Methods:
- Discovery and development of compounds targeting the myristate-binding pocket of BCR-ABL.
- Assessing the ability of these compounds to induce an inactive state of BCR-ABL.
- Evaluating the efficacy of myristate-pocket inhibitors against resistance mutations and in preclinical models.
Main Results:
- Compounds binding to the myristate-binding pocket induce an inactive state of BCR-ABL.
- These inhibitors overcome resistance mutations in the ATP-binding pocket, including the T315I mutation.
- Myristate-pocket inhibitors show synergistic effects with ATP-competitive inhibitors in CML models.
Conclusions:
- Targeting the myristate-binding pocket of BCR-ABL is a promising strategy to overcome imatinib resistance in CML.
- This allosteric inhibition approach can address mutations resistant to ATP-competitive drugs.
- Dual inhibitory strategies combining myristate-pocket and ATP-competitive inhibitors are under clinical investigation.
