Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib

作者：Huang Qinhua^*; Johnson Ted W; Bailey Simon; Brooun Alexei; Bunker Kevin D; Burke Benjamin J; Collins Michael R; Cook Andrew S; Cui J Jean; Dack Kevin N; Deal Judith G; Deng Ya Li; Dinh Dac; Engstrom Lars D; He Mingying; Hoffman Jacqui; Hoffman Robert L; Johnson Patrick S; Kania Robert S; Lam Hieu; Lam Justine L; Le Phuong T; Li Qiuhua; Lingardo Laura; Liu Wei; Lu Melissa West; McTigue Michele; Palmer Cynthia L; Richardson Paul F; Sach Neal W

来源：Journal of Medicinal Chemistry, 2014, 57(4): 1170-1187.

DOI：10.1021/jm401805h

Crizotinib (1), an anaplastic. lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).

• 出版日期2014-2-27