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

BCL-X, 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-X inhibitors exemplified by A-1293102. This molecule contains structural elements of selective BCL-X inhibitor A-1155463 and the dual BCL-X/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-X and both efficiently and selectively killed BCL-X-dependent tumor cells. X-ray crystallographic analysis demonstrated a key hydrogen bonding network in the P2 binding pocket of BCL-X, 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-X inhibitors, and thus serves as a useful tool for biological studies as well as a lead compound for further optimization.