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
  • 1. AbbVie Inc., 1 North Waukegan Rd, North Chicago, Illinois 60064, United States.
PMID: 34141086 DOI: 10.1021/acsmedchemlett.1c00162
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.