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.

Products