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.
Le Wang  1 George A Doherty  1 Andrew S Judd  1 Zhi-Fu Tao  1 T Matthew Hansen  1 Robin R Frey  1 Xiaohong Song  1 Milan Bruncko  1 Aaron R Kunzer  1 Xilu Wang  1 Michael D Wendt  1 John A Flygare  2 Nathaniel D Catron  1 Russell A Judge  1 Chang H Park  1 Shashank Shekhar  1 Darren C Phillips  1 Paul Nimmer  1 Morey L Smith  1 Stephen K Tahir  1 Yu Xiao  1 John Xue  1 Haichao Zhang  1 Phuong N Le  1 Michael J Mitten  1 Erwin R Boghaert  1 Wenqing Gao  1 Peter Kovar  1 Edna F Choo  2 Dolores Diaz  2 Wayne J Fairbrother  2 Steven W Elmore  1 Deepak Sampath  2 Joel D Leverson  1 Andrew James Souers  1
Affiliations
  • 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.
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.

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