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Molecules 2016, 21(11), 1462; doi:10.3390/molecules21111462

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

1
Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
2
Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
3
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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Abstract

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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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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