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

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).