1. Academic Validation
  2. Structure-Based Design of A-1293102, a Potent and Selective BCL-XL Inhibitor

Structure-Based Design of A-1293102, a Potent and Selective BCL-XL Inhibitor

  • ACS Med Chem Lett. 2021 May 12;12(6):1011-1016. doi: 10.1021/acsmedchemlett.1c00162.
Zhi-Fu Tao 1 Xilu Wang 1 Jun Chen 1 Justin P Ingram 1 Sha Jin 1 Russell A Judge 1 Peter J Kovar 1 Chang Park 1 Chaohong Sun 1 Brian D Wakefield 1 Li Zhou 1 Haichao Zhang 1 Steven W Elmore 1 Darren C Phillips 1 Andrew S Judd 1 Joel D Leverson 1 Andrew J Souers 1
Affiliations

Affiliation

  • 1 AbbVie Inc., 1 North Waukegan Rd, North Chicago, Illinois 60064, United States.
Abstract

BCL-XL, an antiapoptotic member of the Bcl-2 Family of proteins, drives tumor survival and maintenance and thus represents a key target for Cancer treatment. Herein we report the rational design of a novel series of selective BCL-XL inhibitors exemplified by A-1293102. This molecule contains structural elements of selective BCL-XL inhibitor A-1155463 and the dual BCL-XL/Bcl-2 inhibitors ABT-737 and navitoclax, while representing a distinct pharmacophore as assessed by an objective cheminformatic evaluation. A-1293102 exhibited picomolar binding affinity to BCL-XL and both efficiently and selectively killed BCL-XL-dependent tumor cells. X-ray crystallographic analysis demonstrated a key hydrogen bonding network in the P2 binding pocket of BCL-XL, while the bent-back moiety achieved efficient occupancy of the P4 pocket in a manner similar to that of navitoclax. A-1293102 represents one of the few distinct structural series of selective BCL-XL inhibitors, and thus serves as a useful tool for biological studies as well as a lead compound for further optimization.

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