3TV6

Human B-Raf Kinase Domain in Complex with a Methoxypyrazolopyridinyl Benzamide Inhibitor

Summary for 3TV6

• Entry DOI: 10.2210/pdb3tv6/pdb
• Related: 3TV4
• Descriptor: Serine/threonine-protein kinase B-raf, 2,6-difluoro-N-(3-methoxy-2H-pyrazolo[3,4-b]pyridin-5-yl)-3-[(propylsulfonyl)amino]benzamide (2 entities in total)
• Functional Keywords: b-raf, kinase, kinase inhibitor, transferase, c-raf, ras, mek, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 71286.09

Authors

Voegtli, W.C.,Sturgis, H.L.,Wu, W.-I. (deposition date: 2011-09-19, release date: 2011-10-05, Last modification date: 2024-02-28)

Primary citation

Wenglowsky, S.,Ren, L.,Ahrendt, K.A.,Laird, E.R.,Aliagas, I.,Alicke, B.,Buckmelter, A.J.,Choo, E.F.,Dinkel, V.,Feng, B.,Gloor, S.L.,Gould, S.E.,Gross, S.,Gunzner-Toste, J.,Hansen, J.D.,Hatzivassiliou, G.,Liu, B.,Malesky, K.,Mathieu, S.,Newhouse, B.,Raddatz, N.J.,Ran, Y.,Rana, S.,Randolph, N.,Risom, T.,Rudolph, J.,Savage, S.,Selby, L.T.,Shrag, M.,Song, K.,Sturgis, H.L.,Voegtli, W.C.,Wen, Z.,Willis, B.S.,Woessner, R.D.,Wu, W.I.,Young, W.B.,Grina, J.
Pyrazolopyridine Inhibitors of B-Raf(V600E). Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors.
ACS Med Chem Lett, 2:342-347, 2011

PubMed Abstract: The V600E mutation of B-Raf kinase results in constitutive activation of the MAPK signaling pathway and is present in approximately 7% of all cancers. Using structure-based design, a novel series of pyrazolopyridine inhibitors of B-Raf(V600E) was developed. Optimization led to the identification of 3-methoxy pyrazolopyridines 17 and 19, potent, selective, and orally bioavailable agents that inhibited tumor growth in a mouse xenograft model driven by B-Raf(V600E) with no effect on body weight. On the basis of their in vivo efficacy and preliminary safety profiles, 17 and 19 were selected for further preclinical evaluation.

PubMed: 24900315
DOI: 10.1021/ml200025q

Experimental method

X-RAY DIFFRACTION (3.3 Å)