American Association for Cancer Research
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Supplementary Materials and Methods and Supplementary Figure Legends from In Vitro and In Vivo Characterization of Irreversible Mutant-Selective EGFR Inhibitors That Are Wild-Type Sparing

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journal contribution
posted on 2023-04-03, 14:09 authored by Robert Tjin Tham Sjin, Kwangho Lee, Annette O. Walter, Aleksandr Dubrovskiy, Michael Sheets, Thia St. Martin, Matthew T. Labenski, Zhendong Zhu, Richland Tester, Russell Karp, Aravind Medikonda, Prasoon Chaturvedi, Yixuan Ren, Henry Haringsma, Jeff Etter, Mitch Raponi, Andrew D. Simmons, Thomas C. Harding, Deqiang Niu, Mariana Nacht, William F. Westlin, Russell C. Petter, Andrew Allen, Juswinder Singh

PDF - 91K, Supplemental Materials and Methods and Legends for Supplementary Figures 1 through 5.



Patients with non–small cell lung carcinoma (NSCLC) with activating mutations in epidermal growth factor receptor (EGFR) initially respond well to the EGFR inhibitors erlotinib and gefitinib. However, all patients relapse because of the emergence of drug-resistant mutations, with T790M mutations accounting for approximately 60% of all resistance. Second-generation irreversible EGFR inhibitors are effective against T790M mutations in vitro, but retain affinity for wild-type EGFR (EGFRWT). These inhibitors have not provided compelling clinical benefit in T790M-positive patients, apparently because of dose-limiting toxicities associated with inhibition of EGFRWT. Thus, there is an urgent clinical need for therapeutics that overcome T790M drug resistance while sparing EGFRWT. Here, we describe a lead optimization program that led to the discovery of four potent irreversible 2,4-diaminopyrimidine compounds that are EGFR mutant (EGFRmut) selective and have been designed to have low affinity for EGFRWT. Pharmacokinetic and pharmacodynamic studies in H1975 tumor–bearing mice showed that exposure was dose proportional resulting in dose-dependent EGFR modulation. Importantly, evaluation of normal lung tissue from the same animals showed no inhibition of EGFRWT. Of all the compounds tested, compound 3 displayed the best efficacy in EGFRL858R/T790M-driven tumors. Compound 3, now renamed CO-1686, is currently in a phase I/II clinical trial in patients with EGFRmut-advanced NSCLC that have received prior EGFR-directed therapy. Mol Cancer Ther; 13(6); 1468–79. ©2014 AACR.

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