3Q96

B-Raf kinase domain in complex with a tetrahydronaphthalene inhibitor

Summary for 3Q96

• Entry DOI: 10.2210/pdb3q96/pdb
• Descriptor: Serine/threonine-protein kinase B-raf, (2S)-N-[3-(2-aminopropan-2-yl)-5-(trifluoromethyl)phenyl]-7-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide (2 entities in total)
• Functional Keywords: design, optimization, potent, orally bioavailable, tetrahydronaphthalene, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : P15056
• Total number of polymer chains: 2
• Total formula weight: 65377.60

Authors

Sintchak, M.D.,Aertgeerts, K.,Yano, J. (deposition date: 2011-01-07, release date: 2011-03-23, Last modification date: 2024-02-21)

Primary citation

Gould, A.E.,Adams, R.,Adhikari, S.,Aertgeerts, K.,Afroze, R.,Blackburn, C.,Calderwood, E.F.,Chau, R.,Chouitar, J.,Duffey, M.O.,England, D.B.,Farrer, C.,Forsyth, N.,Garcia, K.,Gaulin, J.,Greenspan, P.D.,Guo, R.,Harrison, S.J.,Huang, S.C.,Iartchouk, N.,Janowick, D.,Kim, M.S.,Kulkarni, B.,Langston, S.P.,Liu, J.X.,Ma, L.T.,Menon, S.,Mizutani, H.,Paske, E.,Renou, C.C.,Rezaei, M.,Rowland, R.S.,Sintchak, M.D.,Smith, M.D.,Stroud, S.G.,Tregay, M.,Tian, Y.,Veiby, O.P.,Vos, T.J.,Vyskocil, S.,Williams, J.,Xu, T.,Yang, J.J.,Yano, J.,Zeng, H.,Zhang, D.M.,Zhang, Q.,Galvin, K.M.
Design and optimization of potent and orally bioavailable tetrahydronaphthalene raf inhibitors.
J.Med.Chem., 54:1836-1846, 2011

PubMed Abstract: Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.

PubMed: 21341678
DOI: 10.1021/jm101479y

Experimental method

X-RAY DIFFRACTION (3.1 Å)