Novel Selective and Potent EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer.
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 moleculeN-(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 EGFRT790Mover wild-type EGFR. Furthermore, in cell-based tests, DY3002, with an IC50value 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.
Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China. liyanxia001@163.com.|Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China. liyanxia001@163.com.
Yanxia
Y
Li
College of Pharmacy, Dalian Medical University, Dalian 116044, Liaoning Province, China. Songzhen@163.com.
Zhendong
Z
Song
College of Pharmacy, Dalian Medical University, Dalian 116044, Liaoning Province, China. rutin@sina.com.
Yue
Y
Jin
College of Pharmacy, Dalian Medical University, Dalian 116044, Liaoning Province, China. tangzeyao@aliyun.com.
Zeyao
Z
Tang
Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China. Kangjian58@163.com.
Jian
J
Kang
College of Pharmacy, Dalian Medical University, Dalian 116044, Liaoning Province, China. xiaodong.ma@139.com.
Xiaodong
X
Ma
D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003062:Codon; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D003062:Codon; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D066246:ErbB Receptors
EGFR T790M; NSCLC; inhibitor; pyrimidine; resistance