1. Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor
- Author
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Paul Nimmer, Erwin R. Boghaert, Robin R. Frey, Phuong N Le, Andrew J. Souers, Peter Kovar, Wenqing Gao, Deepak Sampath, Dolores Diaz, Haichao Zhang, T. Matthew Hansen, Michael J. Mitten, Stephen K. Tahir, Russell A. Judge, Edna F. Choo, Yu Xiao, Shashank Shekhar, Xiaohong Song, George Doherty, Zhi-Fu Tao, Andrew S. Judd, Wayne J. Fairbrother, Michael D. Wendt, Steven W. Elmore, Kunzer Aaron R, Le Wang, Xilu Wang, Darren C. Phillips, Morey L. Smith, John A. Flygare, John Xue, Joel D. Leverson, Milan Bruncko, Chang H. Park, and Nathaniel D. Catron
- Subjects
Drug ,media_common.quotation_subject ,A-1331852 ,Design elements and principles ,BCL-2 ,Bcl-xL ,Pharmacology ,01 natural sciences ,Biochemistry ,BCL-XL ,Drug Discovery ,media_common ,biology ,010405 organic chemistry ,Drug discovery ,Chemistry ,Organic Chemistry ,apoptosis ,A-1155463 ,Featured Letter ,0104 chemical sciences ,Bioavailability ,010404 medicinal & biomolecular chemistry ,Orally active ,structure-based drug design (SBDD) ,Apoptosis ,biology.protein ,Pharmacophore - Abstract
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.
- Published
- 2020