Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases

摘要: To realize the full potential of targeted protein kinase inhibitors for treatment cancer, it is important to address emergence drug resistance in treated patients. Mutant forms BCR-ABL, KIT, and EGF receptor (EGFR) have been found that confer drugs imatinib, gefitinib, erlotinib. The mutations weaken or prevent binding, interestingly, one most common sites mutation all three kinases a highly conserved “gatekeeper” threonine residue near active site. We identified existing clinical compounds bind inhibit drug-resistant mutant variants ABL, EGFR. Aurora inhibitor VX-680 p38 BIRB-796 imatinib- BMS-354825-resistant ABL(T315I) kinase. KIT/FLT3 SU-11248 potently inhibits imatinib-resistant KIT(V559D/T670I) kinase, consistent with efficacy against gastrointestinal tumors, EGFR EKB-569 CI-1033, but not GW-572016 ZD-6474, gefitinib- erlotinib-resistant EGFR(L858R/T790M) CI-1033 are already trials, our results suggest they should be considered testing gefitinib/erlotinib-resistant non-small cell lung cancer. highlight strategy screening newly find may serve as starting points development next-generation drugs, could used directly treat patients acquired first-generation therapy.