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

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• 作者：Qinhua Huang ; Ted W. Johnson ; Simon Bailey ; Alexei Brooun ; Kevin D. Bunker ; Benjamin J. Burke ; Michael R. Collins ; Andrew S. Cook ; J. Jean Cui ; Kevin N. Dack ; Judith G. Deal ; Ya-Li Deng ; Dac Dinh ; Lars D. Engstrom ; Mingying He ; Jacqui Hoffman ; Robert L. Hoffman ; Patrick S. Johnson ; Robert S. Kania ; Hieu Lam ; Justine L. Lam ; Phuong T. Le ; Qiuhua Li ; Laura Lingardo ; Wei Liu ; Melissa West Lu ; Michele McTigue ; Cynthia L. Palmer ; Paul F. Richardson ; Neal W. Sach ; Hong Shen ; Tod Smeal ; Graham L. Smith ; Albert E. Stewart ; Sergei Timofeevski ; Konstantinos Tsaparikos ; Hui Wang ; Huichun Zhu ; Jinjiang Zhu ; Helen Y. Zou ; Martin P. Edwards
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 27, 2014
• 年：2014
• 卷：57
• 期：4
• 页码：1170-1187
• 全文大小：840K
• 年卷期：v.57,no.4(February 27, 2014)
• ISSN：1520-4804

文摘

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).