Download MendeleyFragment-based discovery of potent ERK2 pyrrolopyrazine inhibitors.
Burdick, D.J., Wang, S., Heise, C., Pan, B., Drummond, J., Yin, J., Goeser, L., Magnuson, S., Blaney, J., Moffat, J., Wang, W., Chen, H.(2015) Bioorg Med Chem Lett 25: 4728-4732
- PubMed: 26338362
- DOI: https://doi.org/10.1016/j.bmcl.2015.08.048
- Primary Citation of Related Structures:
4QP1, 4QP2, 4QP3, 4QP4, 4QP6, 4QP7, 4QP8, 4QP9, 4QPA - PubMed Abstract:
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.
Organizational Affiliation:
Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA 94080, United States. Electronic address: [email protected].
