title: Discovery of a novel class anti-proliferative agents and potential inhibitors of EGFR tyrosine kinases based on 4-anilinotetrahydropyrido[4,3-d]pyrimidine scaffold: Design, synthesis and biological evaluations.
abstract: A novel series of 4-arylamino-6/7-substituted-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines were designed, synthesized and their biological activities as the potential anti-proliferative agents and EGFR kinase inhibitors were evaluated. Both of N-acrylamide fragment in THPPs and 4-aniline groups with substituents played key roles for their significant anti-proliferative activities against four cancer cell lines (HT29, A549, H460 and H1975). Especially inhibitory activity of Gefitinib-resistant H1975 were showed more favorable, which could be observed from compounds 13b, 13c, 13n, 13o, 13p, 13r, 13s, 13u and 24c obviously. By evaluation of inhibiting EGFR and HER2 kinases, seven compounds (13b, 13g, 13n, 13o, 13p, 13r and 13s) showed stronger EGFR potency with IC50 ⩽ 18 nM, which could also be understood by preliminary docking study of 13b with EGFR kinase. In view of the primary SAR, bisarylaniline derivatives (13o, 13p, 13r and 13s) showed obvious improvements on HER2 inhibition, which indicated their being potential EGFR/HER2 dual kinase inhibitors.
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Mingze
authors.initials: M
authors.lastname: Qin
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Shuchun
authors.initials: S
authors.lastname: Guo
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: gongpinggp@126.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011743:Pyrimidines; D066246:ErbB Receptors
keywords: Anti-proliferative agents; EGFR tyrosine kinase inhibitor; Tetrahydropyrido[4,3-d]pyrimidine (THPP)