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The Dawn of Allosteric BCR-ABL1 Drugs: From a Phenotypic Screening Hit to an Approved Drug.

Jacob, Sandra, Teng, Mingxing, Luskin, Marlise, Ding, Qiang, Fabbro, Doriano and Gray, Nathanael (2022) The Dawn of Allosteric BCR-ABL1 Drugs: From a Phenotypic Screening Hit to an Approved Drug. Journal of medicinal chemistry, 65 (11). pp. 7581-7594. ISSN 1520-4804


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.

Item Type: Article
Keywords: Binding Sites Drug Resistance, Neoplasm Fusion Proteins, bcr-abl Humans Leukemia, Myelogenous, Chronic, BCR-ABL Positive Mutation Protein Kinase Inhibitors
Date Deposited: 01 Sep 2023 00:46
Last Modified: 01 Sep 2023 00:46


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