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Molecules 2016, 21(11), 1462;

Novel Selective and Potent EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer

Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
College of Pharmacy, Dalian Medical University, Dalian 116044, Liaoning Province, China
Authors to whom correspondence should be addressed.
Academic Editor: James W. Leahy
Received: 30 September 2016 / Revised: 26 October 2016 / Accepted: 29 October 2016 / Published: 2 November 2016
(This article belongs to the Special Issue Kinase Inhibitor Chemistry)
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Treating patients suffering from EGFR mutant non-small cell lung cancer (NSCLC) with first-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provides excellent response rates. However, approximately 60% of all patients ultimately develop drug resistance due to a second T790M EGFR TKI mutation. In this study, we report the novel molecule N-(3-((5-chloro-2-(4-((1-morpholino)methyl)phenylamino)-4-pyrimidinyl)amino)phenyl)acrylamide (DY3002) to preferentially inhibit the EGFR T790M mutant (EGFRT790M) (IC50 = 0.71 nM) over wild-type EGFR (IC50 = 448.7 nM) in kinase assays. Compared to rociletinib (SI = 21.4) and osimertinib (SI = 40.9), it significantly increased selectivity (SI = 632.0) against EGFRT790M over wild-type EGFR. Furthermore, in cell-based tests, DY3002, with an IC50 value of 0.037 μM, exhibited enhanced inhibitory potency against H1975 cells. Moreover, AO/EB and DAPI staining assays as well as flow cytometer analyses indicated that DY3002 possesses superior biological properties compared to alternatives. In addition, a rat oral glucose tolerance test revealed that treatment with high drug doses (50 mg/kg) of DY3002 did not result in hyperglycemia, suggesting a reduction of side effects in NSCLC patients will be achievable relative to established EGFR inhibitors. In summary, our findings indicate DY3002 as a promising preclinical candidate for effective treatment of patients with EGFRT790M-mutated NSCLC. View Full-Text
Keywords: NSCLC; EGFR T790M; resistance; pyrimidine; inhibitor NSCLC; EGFR T790M; resistance; pyrimidine; inhibitor

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Li, Y.; Song, Z.; Jin, Y.; Tang, Z.; Kang, J.; Ma, X. Novel Selective and Potent EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer. Molecules 2016, 21, 1462.

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