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Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity.

ABSTRACT: A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growth in vivo following multiple doses. A-1155463 thus represents an excellent tool molecule for studying BCL-XL biology as well as a productive lead structure for further optimization.

SUBMITTER: Tao ZF 

PROVIDER: S-EPMC4190639 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity.

Tao Zhi-Fu ZF   Hasvold Lisa L   Wang Le L   Wang Xilu X   Petros Andrew M AM   Park Chang H CH   Boghaert Erwin R ER   Catron Nathaniel D ND   Chen Jun J   Colman Peter M PM   Czabotar Peter E PE   Deshayes Kurt K   Fairbrother Wayne J WJ   Flygare John A JA   Hymowitz Sarah G SG   Jin Sha S   Judge Russell A RA   Koehler Michael F T MF   Kovar Peter J PJ   Lessene Guillaume G   Mitten Michael J MJ   Ndubaku Chudi O CO   Nimmer Paul P   Purkey Hans E HE   Oleksijew Anatol A   Phillips Darren C DC   Sleebs Brad E BE   Smith Brian J BJ   Smith Morey L ML   Tahir Stephen K SK   Watson Keith G KG   Xiao Yu Y   Xue John J   Zhang Haichao H   Zobel Kerry K   Rosenberg Saul H SH   Tse Chris C   Leverson Joel D JD   Elmore Steven W SW   Souers Andrew J AJ  

ACS medicinal chemistry letters 20140826 10

A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, while possessing none of its inherent pharmaceutical liabilities. A-1155463 caused a mechanism-based and reversible thrombocytopenia in mice and inhibited H146 small cell lung cancer xenograft tumor growt  ...[more]

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