Design,synthesis and SAR study of 2-aminopyrimidines with diverse Michael addition acceptors for chemically tuning the potency against EGFRL858R/T790M |
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| Institution: | 1. School of Medicine, Zhejiang University City College, Hangzhou 310015, PR China;2. Zhejiang Province Key Laboratory of Anti-Cancer Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China;1. Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain;2. Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain;3. Área de Farmacología, Nutrición y Bromatología, Unidad Asociada al IQM y al CIAL (CSIC), Departamento de C.C. Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avda. Atenas s/n, 28922 Alcorcón, Spain;4. U.G.C de Metabolismo Óseo, RedinREN del ISC III, Hospital Universitario Central de Asturias, Instituto de Investigaciones Sanitarias del Principado de Asturias, Edificio FINBA, Planta primera F1.1 (Aula 14), Avenida de Roma s/n, 33011 Oviedo, Spain;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, Jiangxi 330004, China;1. Institute of Pharmaceutical Science, China Pharmaceutical University, Nanjing, 210009, PR China;2. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100050, PR China;1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China;2. Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Guangzhou 510000, PR China |
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| Abstract: | The covalent binding nature of irreversible kinase inhibitors potentially increases the severity of “off-target” toxicity. Based on our continual strategy of chemically tuning the Michael addition acceptors, herein, we further explore the relationship among the electronic nature of Michael addition acceptors and EGFRT790M mutation selectivity as well as “off-target” toxicity balance. By perturbing the electronic nature of acrylamide moiety, compound 8a with a chloro-group at the α-position of the Michael addition acceptor was identified. It was found that 8a retained the excellent EGFR L858R/T790M potency (IC50 = 3.9 nM) and exhibited good anti-proliferative activities against the gefitinib-resistant NCI-H1975 cells (IC50 = 0.75 μM). Moreover, 8a displayed a significant EGFRWT selectivity and much weaker inhibitory activity against non-EGFR dependent SW620 cell and COS7. Preliminary study showed that 8a could arrest NCI-H1975 cells in G0/G1 phase. This work provides a promising chemical tuned strategy for balancing the mutant-EGFR potency and selectivity as well as “off-target” toxicity. |
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| Keywords: | NSCLC EGFR Resistant mutants Chemical tuned Michael addition acceptors |
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