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.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston MA, USA. Electronic address: nsgray01@gmail.com.
Nathanael S
NS
Gray
PIQUR Therapeutics AG, Hochbergerstrasse 60C, Basel, Switzerland.
Doriano
D
Fabbro
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D020134:Catalytic Domain; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D019814:Myristic Acid / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D015507:Drugs, Investigational; D008024:Ligands; D047428:Protein Kinase Inhibitors; D019814:Myristic Acid; D000255:Adenosine Triphosphate; D016044:Fusion Proteins, bcr-abl
Allosteric inhibitor; BCR–ABL; Kinase inhibitor; Myristate-pocket binders; T315I gatekeeper mutation