4QP6

Crystal Structure of ERK2 in complex with 5H-pyrrolo[2,3-b]pyrazine

Summary for 4QP6

• Entry DOI: 10.2210/pdb4qp6/pdb
• Related: 4QP1 4QP2 4QP3 4QP4 4QP7 4QP8 4QP9 4QPA
• Descriptor: Mitogen-activated protein kinase 1, 5H-pyrrolo[2,3-b]pyrazine, IMIDAZOLE (3 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytoskeleton, spindle : P28482
• Total number of polymer chains: 2
• Total formula weight: 85562.99

Authors

Yin, J.,Wang, W. (deposition date: 2014-06-22, release date: 2015-09-23, Last modification date: 2015-12-16)

Primary citation

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.
Fragment-based discovery of potent ERK2 pyrrolopyrazine inhibitors.
Bioorg.Med.Chem.Lett., 25:4728-4732, 2015

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.

PubMed: 26338362
DOI: 10.1016/j.bmcl.2015.08.048

Experimental method

X-RAY DIFFRACTION (3.1 Å)