The Dawn of Allosteric BCR-ABL1 Drugs: From a Phenotypic Screening Hit to an Approved DrugClick to copy article linkArticle link copied!
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- Mingxing TengMingxing TengDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United StatesMore by Mingxing Teng
- Marlise R. LuskinMarlise R. LuskinDivision of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United StatesMore by Marlise R. Luskin
- Sandra W. Cowan-JacobSandra W. Cowan-JacobNovartis Institutes for BioMedical Research, Novartis Campus, Basel CH-4056, SwitzerlandMore by Sandra W. Cowan-Jacob
- Qiang Ding
- Doriano Fabbro
- Nathanael S. Gray*Nathanael S. Gray*Email: [email protected]Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, California 94305, United StatesMore by Nathanael S. Gray
Abstract
Chronic myeloid leukemia (CML) is driven by the constitutive activity of the BCR-ABL1 fusion oncoprotein. Despite the great success of drugs that target the BCR-ABL1 ATP-binding site in transforming CML into a manageable disease, emerging resistance point mutations impair inhibitor binding, thereby limiting the effectiveness of these drugs. Recently, allosteric inhibitors that interact with the ABL1 myristate-binding site have been shown to awaken an endogenous regulatory mechanism and reset full-length BCR-ABL1 into an inactive assembled state. The discovery and development of these allosteric inhibitors demonstrates an in-depth understanding of the fundamental regulatory mechanisms of kinases. In this review, we illustrate the structural basis of c-ABL1’s dynamic regulation of autoinhibition and activation, discuss the discovery of allosteric inhibitors and the characterization of their mechanism of action, present the therapeutic potential of dual binding to delay the development of mutation-driven acquired resistance, and suggest key lessons learned from this program.
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