Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-X(L) Inhibitor

[Image: see text] Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-X(L) inhibitor that selectively and potently induces apoptosis in BCL-X(L)-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-X(L) inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp(3)-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-X(L). 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.