Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-X Inhibitor.
Basic Information
ID: ALA4725425
Journal: ACS Med Chem Lett
Title: Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-X Inhibitor.
Authors: Wang L,Doherty GA,Judd AS,Tao ZF,Hansen TM,Frey RR,Song X,Bruncko M,Kunzer AR,Wang X,Wendt MD,Flygare JA,Catron ND,Judge RA,Park CH,Shekhar S,Phillips DC,Nimmer P,Smith ML,Tahir SK,Xiao Y,Xue J,Zhang H,Le PN,Mitten MJ,Boghaert ER,Gao W,Kovar P,Choo EF,Diaz D,Fairbrother WJ,Elmore SW,Sampath D,Leverson JD,Souers AJ
Abstract: Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-X inhibitor that selectively and potently induces apoptosis in BCL-X-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-X inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-X. 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.
CiteXplore: 33062160
DOI: 10.1021/acsmedchemlett.9b00568
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