Toward discovery of mutant EGFR inhibitors; Design,synthesis and in vitro biological evaluation of potent 4-arylamino-6-ureido and thioureido-quinazoline derivatives |
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| Affiliation: | 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA;2. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave., SGM 628, Boston, MA 02115, USA;3. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Misr International University, Km 28 Cairo-Ismailia Road (Ahmed Orabi District) Cairo, Egypt;4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA;5. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566 Cairo, Egypt;1. School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China;2. Key Laboratory of Jiangxi Province Natural Active Pharmaceutical Ingredients, College of Chemistry and Biology Engineering, Yichun University, Yichun 336000, PR China;1. College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China;2. Guangzhou Institute of Biomedicine and Health, Chinese Academy of Science, Guangzhou 510530, China;3. Beijing Dalitai Pharmaceutical Technology Co. Ltd, Beijing 100176, China;1. Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, PR China;2. Experimental Chemistry Center, College of Chemistry, Beijing Normal University, Beijing Normal University, Beijing, 100875, PR China;3. Shanxi Institute of Technology, Yangquan, Shanxi, 045000, PR China;1. School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang 330013, PR China;2. School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, PR China;3. School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, PR China |
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| Abstract: | A new series of 4-anilinoquinazolines with C-6 ureido and thioureido side chains and various substituents at the C-4 anilino moiety was designed, synthesized and evaluated as wild type (WT) and mutant EGFR inhibitors. Most of the compounds inhibited EGFR kinase wild type (EGFR WT) with IC50 values in the low nanomolar range (<0.495–9.05 nM) and displayed more potent cytotoxic effect in BaF/3 expressing EGFR WT than reference compound gefitinib. The anti-proliferative effect of all synthesized compounds against gefitinib insensitive double mutant cell lines Ba/F3 expressing Del19/T790M and Ba/F3 expressing L858R/T790M were assayed. Compounds 4d, 6f, 7e showed significant inhibition (IC50 = 1.76–2.38 μM) in these mutant lines and significant Her2 enzyme inhibition (IC50 = 19.2–40.6 nM) compared to lapatinib (60.1 nM). The Binding mode of compounds 6d, 6f, 7a, 7b and 8b were demonstrated. Furthermore, growth inhibition against gefitinib insensitive cell lines PC9-GR4 (Del19/T790M) were tested, compounds 6f and 7e showed about eight and three folds respectively greater potency than gefitinib. Our structure–activity relationships (SAR) studies suggested that presence of ethyl piperidino urea/thiourea at 6-position and bulky group of (3-chloro-4-(3-fluorobenzyloxy)phenyl)amino at 4-position of quinazoline may serve as promising scaffold for developing inhibitors against wild type and mutant EGFR. |
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| Keywords: | EGFR inhibitors Quinazolines Urea derivatives Synthesis EGFR-Her2 dual inhibitors EGFR L858R/T790 mutant EGFR Del19/T790M mutant |
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