title: Triazole-dithiocarbamate based selective lysine specific demethylase 1 (LSD1) inactivators inhibit gastric cancer cell growth, invasion, and migration.
abstract: Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression. The up-regulated LSD1's expression has been reported in several malignant tumors. In the current study, we designed and synthesized five series of 1,2,3-triazole-dithiocarbamate hybrids and screened their inhibitory activity toward LSD1. We found that some of these compounds, especially compound 26, exhibited the most specific and robust inhibition of LSD1. Interestingly, compound 26 also showed potent and selective cytotoxicity against LSD1 overexpressing gastric cancer cell lines MGC-803 and HGC-27, as well as marked inhibition of cell migration and invasion, compared to 2-PCPA. Furthermore, compound 26 effectively reduced the tumor growth bared by human gastric cancer cells in vivo with no signs of adverse side effects. These findings suggested that compound 26 deserves further investigation as a lead compound in the treatment of LSD1 overexpressing gastric cancer.
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; New Drug Research & Development Center, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Zheng
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; New Drug Research & Development Center, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Ying-Chao
authors.initials: YC
authors.lastname: Duan
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; New Drug Research & Development Center, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Jin-Lian
authors.initials: JL
authors.lastname: Ma
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; New Drug Research & Development Center, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Rui-Min
authors.initials: RM
authors.lastname: Xu
authors.affiliation: Departments of Urology, Pharmacology and Pharmaceutical Sciences, University of California, Irvine, Orange, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zi
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; New Drug Research & Development Center, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Wen-Lei
authors.initials: WL
authors.lastname: Lv
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; New Drug Research & Development Center, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Meng-Meng
authors.initials: MM
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; New Drug Research & Development Center, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Xian-Wei
authors.initials: XW
authors.lastname: Ye
authors.affiliation: Department of Pharmaceutical Sciences, University of California, Irvine, USA.
authors.forename: Shun
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutical Sciences, University of California, Irvine, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mobley
authors.affiliation: The College of Chemistry and Molecular Engineering, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Zhu
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; New Drug Research & Development Center, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Jun-Wei
authors.initials: JW
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; New Drug Research & Development Center, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Jin-Feng
authors.initials: JF
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; New Drug Research & Development Center, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Zhi-Ru
authors.initials: ZR
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; New Drug Research & Development Center, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhao
authors.affiliation: School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; New Drug Research & Development Center, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D013859:Thiocarbamates; D014230:Triazoles; D056466:Histone Demethylases; C495195:KDM1A protein, human