2. Academic Validation
  3. Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib

Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib

  • J Med Chem. 2014 Feb 27;57(4):1170-87. doi: 10.1021/jm401805h.
Qinhua Huang 1,  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
Affiliations

Affiliation

  • 1 La Jolla Laboratories, Pfizer Worldwide Research and Development , 10770 Science Center Drive, San Diego, California 92121, United States.
PMID: 24432909 DOI: 10.1021/jm401805h
Abstract

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).

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