3SKC

Human B-Raf Kinase in Complex with an Amide Linked Pyrazolopyridine Inhibitor

Summary for 3SKC

• Entry DOI: 10.2210/pdb3skc/pdb
• Descriptor: Serine/threonine-protein kinase B-raf, 2,6-difluoro-N-[(5S)-3-methoxy-5H-pyrazolo[3,4-b]pyridin-5-yl]-3-[(phenylsulfonyl)amino]benzamide (2 entities in total)
• Functional Keywords: kinase, atp-competitive inhibitor, transferase, ras, mek, c-raf, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (By similarity): P15056
• Total number of polymer chains: 2
• Total formula weight: 71354.12

Authors

Voegtli, W.C.,Sturgis, H.L. (deposition date: 2011-06-22, release date: 2011-08-17, Last modification date: 2024-02-28)

Primary citation

Wenglowsky, S.,Ahrendt, K.A.,Buckmelter, A.J.,Feng, B.,Gloor, S.L.,Gradl, S.,Grina, J.,Hansen, J.D.,Laird, E.R.,Lunghofer, P.,Mathieu, S.,Moreno, D.,Newhouse, B.,Ren, L.,Risom, T.,Rudolph, J.,Seo, J.,Sturgis, H.L.,Voegtli, W.C.,Wen, Z.
Pyrazolopyridine inhibitors of B-RafV600E. Part 2: structure-activity relationships.
Bioorg.Med.Chem.Lett., 21:5533-5537, 2011

PubMed Abstract: Structure-activity relationships around a novel series of B-Raf(V600E) inhibitors are reported. The enzymatic and cellular potencies of inhibitors derived from two related hinge-binding groups were compared and3-methoxypyrazolopyridine proved to be superior. The 3-alkoxy group of lead B-Raf(V600E) inhibitor 1 was extended and minimally affected potency. The propyl sulfonamide tail of compound 1, which occupies the small lipophilic pocket formed by an outward shift of the αC-helix, was expanded to a series of arylsulfonamides. X-ray crystallography revealed that this lipophilic pocket unexpectedly enlarges to accommodate the bulkier aryl group.

PubMed: 21802293
DOI: 10.1016/j.bmcl.2011.06.097

Experimental method

X-RAY DIFFRACTION (3.2 Å)