Design and optimization of potent and orally bioavailable tetrahydronaphthalene Raf inhibitors.

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Gould AE, Adams R, Adhikari S, Aertgeerts K, Afroze R, Blackburn C, Calderwood EF, Chau R, Chouitar J, Duffey MO, England DB, Farrer C, Forsyth N, Garcia K, Gaulin J, Greenspan PD, Guo R, Harrison SJ, Huang SC, Iartchouk N, Janowick D, Kim MS, Kulkarni B, Langston SP, Liu JX, Ma LT, Menon S, Mizutani H, Paske E, Renou CC, Rezaei M, Rowland RS, Sintchak MD, Smith MD, Stroud SG, Tregay M, Tian Y, Veiby OP, Vos TJ, Vyskocil S, Williams J, Xu T, Yang JJ, Yano J, Zeng H, Zhang DM, Zhang Q, Galvin KM

Design and optimization of potent and orally bioavailable tetrahydronaphthalene Raf inhibitors.

J Med Chem. 2011 Mar 24;54(6):1836-46. doi: 10.1021/jm101479y. Epub 2011 Feb 22.

PubMed ID

21341678 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Sorafenib	RAF proto-oncogene serine/threonine-protein kinase	IC 50 (nM)	6	N/A	N/A	Details