Discovery of 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)py rido[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

作者：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

来源：Journal of Medicinal Chemistry, 2015, 58(10): 4165-4179.

DOI：10.1021/acs.jmedchem.5b00067

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 tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS Mutation. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild. type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.

• 出版日期2015-5-28