Structure activity relationship and modeling studies of inhibitors of lysine specific demethylase 1.

Structure activity relationship and modeling studies of inhibitors of lysine specific demethylase 1.

Chao Zhou, Fangrui Wu, Lianghao Lu, Liping Wei, Eric Pai, Yuan Yao, Yongcheng Song

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.

2017

DOI: 10.1371/journal.pone.0170301

PLoS ONE

Public Library of Science (PLoS)

Science, Medicine

EN