2-Oxo-3,4-dihydropyrimido[4,5-d] pyrimidines as new reversible inhibitors of EGFR C797S (Cys797 to Ser797) mutant |
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| Institution: | 1. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, Guangzhou 510632, China;2. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;3. Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China;4. Department of Biochemistry and Biophysics, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China;1. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China;2. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;3. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;4. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China;5. School of Pharmacy, Nanchang University, 461 Bayi Road, Nanchang 330006, China;1. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China;2. College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China;1. Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China;2. Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China;3. Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China;4. Fengnan District Hospital, Tangshan 063300, China;1. College of Pharmacy, Dalian Medical University, Dalian, 116044, PR China;2. School of Pharmaceutical Engineering, Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang, 110016, PR China;1. Department of Medicinal Chemistry, School of Pharmacy, Xi′an Jiaotong University, Xi′an, Shaanxi 710061, PR China;2. Department of Pharmacology, School of Basic Medical Science, Xi′an Jiaotong University, Xi′an, Shaanxi 710061, PR China;1. Department of Medicinal Chemistry, School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, PR China;2. Department of Pharmacology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi 710061, PR China |
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| Abstract: | Extensive structure-activity relationships (SARs) study of JND3229 was conducted to yield a series of new reversible 2-oxo-3,4-dihydropyrimido4,5-d]pyrimidine privileged scaffold as EGFRC797S inhibitors. One of the most potent compound 6i potently suppressed EGFRL858R/T790M/C797S kinase with an IC50 value of 3.1 nmol/L, and inhibited the proliferation of BaF3 cells harboring EGFRL858R/T790M/C797S and EGFR19D/T790M/C797S mutants with IC50 values of 290 nmol/L and 316 nmol/L, respectively. Further, 6i dose-dependently induced suppression of the phosphorylation of EGFRL858R/T790M/C797S and EGFR19D/T790M/C797S in BaF3 cells. Compound 6i may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients. |
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| Keywords: | SARs Clinical resistance Fourth-generation inhibitors |
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