Fragment-based discovery of potent ERK2 pyrrolopyrazine inhibitors
Copyright policy )Fragment-based discovery of potent ERK2 pyrrolopyrazine inhibitors
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.
- GENENTECH INC United States
Mitogen-Activated Protein Kinase 1, Models, Molecular, Dose-Response Relationship, Drug, Molecular Structure, Organic Chemistry, Clinical Biochemistry, Pharmaceutical Science, Biochemistry, Structure-Activity Relationship, Pyrazines, Drug Discovery, Molecular Medicine, Humans, Pyrroles, Molecular Biology
Mitogen-Activated Protein Kinase 1, Models, Molecular, Dose-Response Relationship, Drug, Molecular Structure, Organic Chemistry, Clinical Biochemistry, Pharmaceutical Science, Biochemistry, Structure-Activity Relationship, Pyrazines, Drug Discovery, Molecular Medicine, Humans, Pyrroles, Molecular Biology
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