Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells.

doi:10.1021/acs.jmedchem.5b00067

Article

Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells.

Journal of medicinal chemistry - 28 May 2015

Henry James R, Kaufman Michael D, Peng Sheng-Bin, Ahn Yu Mi, Caldwell Timothy M, Vogeti Lakshminarayana, Telikepalli Hanumaiah, Lu Wei-Ping, Hood Molly M, Rutkoski Thomas J, Smith Bryan D, Vogeti Subha, Miller David, Wise Scott C, Chun Lawrence, Zhang Xiaoyi, Zhang Youyan, Kays Lisa, Hipskind Philip A, Wrobleski Aaron D, Lobb Karen L, Clay Julia M, Cohen Jeffrey D, Walgren Jennie L, McCann Denis, Patel Phenil, Clawson David K, Guo Sherry, Manglicmot Danalyn, Groshong Chris, Logan Cheyenne, Starling James J, Flynn Daniel L

Abstract excerpt

The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of...

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Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells.

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