Fragment-based discovery of potent ERK2 pyrrolopyrazine inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Burdick, Daniel J.¹  Wang, Shumei¹  Heise, Christopher²  Pan, Borlan³  Drummond, Jake²  Yin, JianPing³  Goeser, Lauren¹  Magnuson, Steven¹  Blaney, Jeff⁴  Moffat, John²  Wang, Weiru³  Chen, Huifen⁴ 

[1] Genentech Inc, Dept Discovery Chem, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Biochem Pharmacol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Biol Struct, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Computat Chem, San Francisco, CA 94080 USA

关键词: ERK2;    Pyrrolopyrazine;    Fragment-based;    Extracellular-regulated kinase;   

DOI  :  10.1016/j.bmcl.2015.08.048

来源: Elsevier

【 摘 要 】

A fragment-based lead discovery approach was used to discover novel ERK2 inhibitors. The crystal structure of N-benzyl-9H-purin-6-amine 1 in complex with ERK2 elucidated its hinge-binding mode. In addition, the simultaneous binding of an imidazole molecule adjacent to 1 suggested a direction for fragment expansion. Structure-based core hopping applied to 1 led to 5H-pyrrolo[3,2-b] pyrazine (3) that afforded direct vectors to probe the pockets of interest while retaining the essential hinge binding elements. Utilizing the new vectors for SAR exploration, the new core 3 was quickly optimized to compound 39 resulting in a greater than 6600-fold improvement in potency. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

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