Structure-Based Design of A-1293102, a Potent and Selective BCL-X<sub>L</sub> Inhibitor
Zhi‐Fu Tao, Xilu Wang, Jun Chen, Justin P. Ingram, Sha Jin, Russell A. Judge, Peter Kovar, Chang Park, Chaohong Sun, Brian D. Wakefield, Li Zhou, Haichao Zhang, Steven W. Elmore, Darren C. Phillips, Andrew S. Judd, Joel D. Leverson, Andrew J. Souers
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.