Discovery of allosteric BCR-ABL inhibitors from phenotypic screen to clinical candidate.
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.
['Gray|Nathanael S|NS|', 'Fabbro|Doriano|D|']
D000255:Adenosine Triphosphate D000494:Allosteric Regulation D000818:Animals D001665:Binding Sites D001667:Binding, Competitive D020134:Catalytic Domain D055808:Drug Discovery D004353:Drug Evaluation, Preclinical D015507:Drugs, Investigational D016044:Fusion Proteins, bcr-abl D006801:Humans D008024:Ligands D008958:Models, Molecular D008968:Molecular Conformation D019814:Myristic Acid D047428:Protein Kinase Inhibitors
Allosteric inhibitor BCR–ABL Kinase inhibitor Myristate-pocket binders T315I gatekeeper mutation