title: Structural optimization and structure-activity relationships of N2-(4-(4-Methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine derivatives, a new class of reversible kinase inhibitors targeting both EGFR-activating and resistance mutations.
abstract: This paper describe the structural optimization of a hit compound, N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine (1), which is a reversible kinase inhibitor targeting both EGFR-activating and drug-resistance (T790M) mutations but has poor binding affinity. Structure-activity relationship studies led to the identification of 9-cyclopentyl-N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine (9e) that exhibits significant in vitro antitumor potency against the non-small-cell lung cancer (NSCLC) cell lines HCC827 and H1975, which harbor EGFR-activating and drug-resistance mutations, respectively. Compound 9e was further assessed for potency and selectivity in enzymatic assays and in vivo anti-NSCLC studies. The results indicated that compound 9e is a highly potent kinase inhibitor against both EGFR-activating and resistance mutations and has good kinase spectrum selectivity across the kinome. In vivo, oral administration of compound 9e at a dose of 5 mg/kg caused rapid and complete tumor regression in a HCC827 xenograft model, and an oral dose of 50 mg/kg initiated a considerable antitumor effect in an H1975 xenograft model.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Yang
authors.forename: Li-Jiao
authors.initials: LJ
authors.lastname: Wang
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.forename: Ren-Lin
authors.initials: RL
authors.lastname: Zheng
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Pan
authors.initials: P
authors.lastname: Ji
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Zhang
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Wang
authors.forename: Xing-Dong
authors.initials: XD
authors.lastname: Lin
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Li
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D007150:Immunohistochemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009154:Mutation; D010879:Piperazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011687:Purines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: C578475:N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011687:Purines; D066246:ErbB Receptors