Identification of 1-(3-(6,7-Dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea Hydrochloride (CEP-32496), a Highly Potent and Orally Efficacious Inhibitor
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- 作者：Martin W. Rowbottom ; Raffaella Faraoni ; Qi Chao ; Brian T. Campbell ; Andiliy G. Lai ; Eduardo Setti ; Maiko Ezawa ; Kelly G. Sprankle ; Sunny Abraham ; Lan Tran ; Brian Struss ; Michael Gibney ; Robert C. Armstrong ; Ruwanthi N. Gunawardane ; Ronald R. Nepomuceno ; Ianina Valenta ; Helen Hua ; Michael F. Gardner ; Merryl D. Cramer ; Dana Gitnick ; Darren E. Insko ; Julius L. Apuy ; Susan Jones-Bolin ; Arup K. Ghose ; Torsten Herbertz ; Mark A. Ator ; Bruce D. Dorsey ; Bruce Ruggeri ; Michael Williams ; Shripad Bhagwat ; Joyce James ; Mark W. Holladay
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：February 9, 2012
- 年：2012
- 卷：55
- 期：3
- 页码：1082-1105
- 全文大小：851K
- 年卷期：v.55,no.3(February 9, 2012)
- ISSN：1520-4804
文摘
The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAFV600E results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAFV600E inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRAFV600E-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAFV600E versus those containing wild-type BRAF. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRAFV600E-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.