title: Synthesis and investigation of novel 6-(1,2,3-triazol-4-yl)-4-aminoquinazolin derivatives possessing hydroxamic acid moiety for cancer therapy.
abstract: By merging the critical pharmacophore of EGFR/HER2 and HDAC inhibitors into one compound, a novel series of EGFR, HER-2, and HDAC multitarget inhibitors were synthesized. Compounds 9a-l contained 4-anilinoquinazolines with C-6 triazole-linked long alkyl chains of hydroxamic acid and displayed excellent inhibition against these enzymes (compound 9d exhibited the best inhibitory potency on wild-type EGFR, HDAC1, and HDAC6 with IC50values 0.12nM, 0.72nM and 3.2nM individually). Furthermore, compounds 9b and 9d potently inhibited proliferation of five human cancer cell lines (with IC50values between 0.49 and 8.76μM). Further mechanistic study revealed that compound 9d also regulated the phosphorylation of EGFR and HER2 and histone H3 hyperacetylation on the cellular level and induced remarkable apoptosis in BT-474 cells. Therefore, our study suggested that a system network-based multi-target drug design strategy might provided an alternate drug design method, by taking into account the synergy effect of EGFR, HER-2 and HDAC.
authors: Department of Chemistry, Tsinghua University, Beijing 100084, PR China; The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
authors: Chao
authors: C
authors: Ding
authors: The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
authors: Shaopeng
authors: S
authors: Chen
authors: Shenzhen Technology and Engineering Laboratory for Personalized Cancer Diagnostics and Therapeutics, Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, PR China.
authors: Cunlong
authors: C
authors: Zhang
authors: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States.
authors: Guangnan
authors: G
authors: Hu
authors: Department of Chemistry, Tsinghua University, Beijing 100084, PR China; The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
authors: Wei
authors: W
authors: Zhang
authors: The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
authors: Lulu
authors: L
authors: Li
authors: Shenzhen Technology and Engineering Laboratory for Personalized Cancer Diagnostics and Therapeutics, Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, PR China.
authors: Yu Zong
authors: YZ
authors: Chen
authors: Department of Chemistry, Tsinghua University, Beijing 100084, PR China; The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China. Electronic address: tancy@sz.tsinghua.edu.cn.
authors: Chunyan
authors: C
authors: Tan
authors: The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; School of Medicine, Tsinghua University, Beijing 100084, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
authors: Yuyang
authors: Y
authors: Jiang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D049452:Green Fluorescent Proteins / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D049452:Green Fluorescent Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D014230:Triazoles; C573775:4-aminoquinazoline; C485184:enhanced green fluorescent protein; C508053:ERBB2 protein, human
keywords: EGFR; HDAC; HER2; Multitarget; Resistance; Synergy