E-viri
PDF
Recenzirano
Odprti dostop
-
Wang, Le; Doherty, George A; Judd, Andrew S; Tao, Zhi-Fu; Hansen, T. Matthew; Frey, Robin R; Song, Xiaohong; Bruncko, Milan; Kunzer, Aaron R; Wang, Xilu; Wendt, Michael D; Flygare, John A; Catron, Nathaniel D; Judge, Russell A; Park, Chang H; Shekhar, Shashank; Phillips, Darren C; Nimmer, Paul; Smith, Morey L; Tahir, Stephen K; Xiao, Yu; Xue, John; Zhang, Haichao; Le, Phuong N; Mitten, Michael J; Boghaert, Erwin R; Gao, Wenqing; Kovar, Peter; Choo, Edna F; Diaz, Dolores; Fairbrother, Wayne J; Elmore, Steven W; Sampath, Deepak; Leverson, Joel D; Souers, Andrew James
ACS medicinal chemistry letters, 10/2020, Letnik: 11, Številka: 10Journal Article
Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-XL inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp3-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-XL. 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.
