title: Design, synthesis, and structure-activity relationship of novel LSD1 inhibitors based on pyrimidine-thiourea hybrids as potent, orally active antitumor agents.
abstract: Histone lysine specific demethylase 1 (LSD1) was reported to be overexpressed in several human cancers and recognized as a promising anticancer drug target. In the current study, we designed and synthesized a novel series of pyrimidine-thiourea hybrids and evaluated their potential LSD1 inhibitory effect. One of the compounds, 6b, containing a terminal alkyne appendage, was shown to be the most potent and selective LSD1 inhibitor in vitro and exhibited strong cytotoxicity against LSD1 overexpressed gastric cancer cells. Compound 6b also showed marked inhibition of cell migration and invasion as well as significant in vivo tumor suppressing and antimetastasis role, without significant side effects by oral administration. Our findings indicate that the pyrimidine-thiourea-based LSD1 inactivator may serve as a leading compound targeting LSD1 overexpressed cancers.
authors.affiliation: Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, and School of Pharmaceutical Sciences, Zhengzhou University , 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Ma
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Zheng
authors.forename: Sai-Qi
authors.initials: SQ
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Zhi-Ru
authors.initials: ZR
authors.lastname: Wang
authors.forename: Lu-Ping
authors.initials: LP
authors.lastname: Pang
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.forename: Jun-Wei
authors.initials: JW
authors.lastname: Wang
authors.forename: Lina
authors.initials: L
authors.lastname: Ding
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.forename: Biao
authors.initials: B
authors.lastname: Hu
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Zhang
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Wang
authors.forename: Zhi-Jian
authors.initials: ZJ
authors.lastname: Wang
authors.forename: Wen
authors.initials: W
authors.lastname: Zhao
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Liu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D056466:Histone Demethylases; C495195:KDM1A protein, human; D013890:Thiourea; C030986:pyrimidine