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Applications
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In NSCLC cells expressing mutant EGFR (HCC827, PC9, HCC827-EPR and NCI-H1975), CO-1686 potently inhibited EGFR phosphorylation, with the IC50 values ranging from 62 to 187 nM. Moreover, CO-1686 selectively inhibited growth of NSCLC cells harboring mutant EGFR (GI50 = 7 ~ 32 nM) and induced apoptosis. In addition, CO-1686-resistant NSCLC cells showed signs of epithelial-mesenchymal transition and increased sensitivity to AKT inhibitors.
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Applications
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In all NSCLC EGFR mutant xenograft models, CO-1686 significantly inhibited tumor growth in a dose-dependent manner. In nude mice bearing NCI-H1975 or LUM1868 cells, CO-1686 caused tumor regressions. In the NCI-H1975 model, CO-1686 resulted in tumor regressions either given as 100 mg/kg once daily or as 50 mg/kg twice daily. Moreover, there was no significant change in body weight observed for these 2 dosing schedules.
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References:
[1]. Walter AO, Sjin RT, Haringsma HJ, Ohashi K, Sun J, Lee K, Dubrovskiy A, Labenski M, Zhu Z, Wang Z, Sheets M, St Martin T, Karp R, van Kalken D, Chaturvedi P, Niu D, Nacht M, Petter RC, Westlin W, Lin K, Jaw-Tsai S, Raponi M, Van Dyke T, Etter J, Weaver Z, Pao W, Singh J, Simmons AD, Harding TC, Allen A. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov. 2013 Dec;3(12):1404-15.
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