Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor
- ACS Med Chem Lett. 2020 Mar 30;11(10):1829-1836. doi: 10.1021/acsmedchemlett.9b00568.
- 1. AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
- 2. Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces Apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-XL inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp3-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-XL. A-1331852 has since been used as a critical tool molecule for further exploring Bcl-2 family Protein Biology, while also representing an attractive entry into a drug discovery program.
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Cat. No.Product NameDescriptionTargetResearch Area
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Research Areas: Cancer