Discovery of a potent dual ALK and EGFR T790M inhibitor

European Journal of Medicinal Chemistry
Jaebong JangNathanael S Gray

Abstract

The mutational activations of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) are validated oncogenic events and the targets of approved drugs to treat non-small cell lung cancer (NSCLC). Here we report highly potent dual small molecule inhibitors of both ALK and EGFR, particularly the T790M mutant which confers resistance to first generation EGFR inhibitors. Dual ALK/EGFR inhibitors may provide an efficient approach to prevent resistance that arises as a consequence of clinically reported reciprocal activation mechanisms. Our lead compound 7c displayed remarkable inhibitory activities against both ALK and EGFR in enzymatic and cellular assays. We demonstrate that 7c is capable of recapitulating the signaling effects and antiproliferative activity of combined treatment with the approved ALK inhibitor ceritinib and T790M EGFR inhibitor osimertinib against patient-derived non-small cell lung cancer cell line, DFCI032 which harbors both EML4-ALK and activated EGFR.

Citations

Aug 7, 2018·Expert Review of Anticancer Therapy·Ilaria AttiliRafael Rosell
Mar 1, 2019·ChemMedChem·Avick Kumar GhoshWenshe Ray Liu
Jan 10, 2020·Chemical Communications : Chem Comm·Shang-Zheng SunHui-Xiong Dai
Aug 14, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Yunju NamTaebo Sim
Apr 28, 2021·Expert Review of Anticancer Therapy·Giuseppe BronteLucio Crinò
Apr 4, 2020·Journal of Medicinal Chemistry·David E HeppnerMichael J Eck

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