TCPs: privileged scaffolds for identifying potent LSD1 inhibitors for cancer therapy.
Since the first lysine-specific demethylase (KDM), lysine-specific demethylase 1 (LSD1), was characterized in 2004, several families of KDMs have been identified. LSD1 can specifically demethylate H3K4me1/2, H3K9me1/2 as well as some nonhistone substrates. It has been demonstrated to be an oncogene as well as a drug target. Hence, tens of small-molecule LSD1 inhibitors have been designed, synthesized and applied for cancer treatment. However, the two LSD1 inhibitors that have been advanced into early phase clinical trials are trans-2-phenylcyclopropylamine (TCP) derivatives, which indicate that TCP is a druggable scaffold for LSD1 inhibitor. Here, we review the design, synthesis and properties of reported TCP-based LSD1 inhibitors as well as their biological roles.
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; Co-innovation Center of Henan Province for New drug R&D & Preclinical Safety; Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
Yi-Chao
YC
Zheng
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; Co-innovation Center of Henan Province for New drug R&D & Preclinical Safety; Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
Bin
B
Yu
College of Pharmacy & Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York, NY 11439, USA.
Zhe-Sheng
ZS
Chen
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; Co-innovation Center of Henan Province for New drug R&D & Preclinical Safety; Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
Ying
Y
Liu
Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; Co-innovation Center of Henan Province for New drug R&D & Preclinical Safety; Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
Hong-Min
HM
Liu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008745:Methylation; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011499:Protein Processing, Post-Translational; D013329:Structure-Activity Relationship; D014191:Tranylcypromine / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D014191:Tranylcypromine; D056466:Histone Demethylases; C495195:KDM1A protein, human
LSD1; cancer; inhibitor; trans-2-phenylcyclopropylamine