title: Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors.
abstract: We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells (EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmacokinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f are promising candidates for further studies.
authors: Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors: Long
authors: L
authors: Zhang
authors: Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors: Yingying
authors: Y
authors: Yang
authors: Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors: Haojie
authors: H
authors: Zhou
authors: Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors: Qingmei
authors: Q
authors: Zheng
authors: Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors: Yuhao
authors: Y
authors: Li
authors: Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors: Shansong
authors: S
authors: Zheng
authors: Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors: Shuyong
authors: S
authors: Zhao
authors: Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China.
authors: Dong
authors: D
authors: Chen
authors: Shandong Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co, Ltd, 243 Gong Ye Bei Road, Jinan 250100, Shandong Province, PR China. Electronic address: chuanwen.fan@qilu-pharma.com.
authors: Chuanwen
authors: C
authors: Fan
mesh_terms: D000077716:Afatinib; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D066246:ErbB Receptors
keywords: A-431; EGFR-T790M; H1975; HCC827; Quinazoline derivatives