Structure activity relationship and modeling studies of inhibitors of lysine specific demethylase 1.
Post-translational modifications of histone play important roles in gene transcription. Aberrant methylation of histone lysine sidechains have been often found in cancer. Lysine specific demethylase 1 (LSD1), which can demethylate histone H3 lysine 4 (H3K4) and other proteins, has recently been found to be a drug target for acute myeloid leukemia. To understand structure activity/selectivity relationships of LSD1 inhibitors, several series of cyclopropylamine and related compounds were synthesized and tested for their activities against LSD1 and related monoamine oxidase (MAO) A and B. Several cyclopropylamine containing compounds were found to be highly potent and selective inhibitors of LSD1. A novel series cyclopropylimine compounds also exhibited strong inhibitory activity against LSD1. Structure activity relationships (SAR) of these compounds are discussed. Docking studies were performed to provide possible binding models of a representative compound in LSD1 and MAO-A. Moreover, these modeling studies can rationalize the observed SARs and selectivity.
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, United States of America.
Chao
C
Zhou
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, United States of America.
Fangrui
F
Wu
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, United States of America.
Lianghao
L
Lu
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, United States of America.
Liping
L
Wei
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, United States of America.
Eric
E
Pai
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, United States of America.
Yuan
Y
Yao
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, United States of America.
Yongcheng
Y
Song
D003521:Cyclopropanes / Q000737:chemistry / Q000494:pharmacology; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D013329:Structure-Activity Relationship
D003521:Cyclopropanes; D006657:Histones; D008996:Monoamine Oxidase Inhibitors; C067351:cyclopropylamine; D056466:Histone Demethylases; D008995:Monoamine Oxidase