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Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor.

ABSTRACT: 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.

SUBMITTER: Wang L 

PROVIDER: S-EPMC7549103 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-X<sub>L</sub> Inhibitor.

Wang Le L   Doherty George A GA   Judd Andrew S AS   Tao Zhi-Fu ZF   Hansen T Matthew TM   Frey Robin R RR   Song Xiaohong X   Bruncko Milan M   Kunzer Aaron R AR   Wang Xilu X   Wendt Michael D MD   Flygare John A JA   Catron Nathaniel D ND   Judge Russell A RA   Park Chang H CH   Shekhar Shashank S   Phillips Darren C DC   Nimmer Paul P   Smith Morey L ML   Tahir Stephen K SK   Xiao Yu Y   Xue John J   Zhang Haichao H   Le Phuong N PN   Mitten Michael J MJ   Boghaert Erwin R ER   Gao Wenqing W   Kovar Peter P   Choo Edna F EF   Diaz Dolores D   Fairbrother Wayne J WJ   Elmore Steven W SW   Sampath Deepak D   Leverson Joel D JD   Souers Andrew James AJ  

ACS medicinal chemistry letters 20200330 10

Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-X<sub>L</sub> inhibitor that selectively and potently induces apoptosis in BCL-X<sub>L</sub>-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-X<sub>L</sub> inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp<sup>3</sup>-rich moieties capable of generating highly produc  ...[more]

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