1. Academic Validation
  2. Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor

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

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.

Figures
Products