Date Published: February 3, 2017
Publisher: Public Library of Science
Author(s): Chao Zhou, Fangrui Wu, Lianghao Lu, Liping Wei, Eric Pai, Yuan Yao, Yongcheng Song, A Ganesan.
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.
Gene transcription is regulated by post translational modifications of histone proteins, which mostly include methylation and acetylation of a lysine or arginine sidechain. The resulting histone steric and/or electrostatic alterations lead to the formation of a transcription protein complex that directly controls gene expression. Recently, aberrant histone modifications are frequently observed in many types of cancer and histone modifying enzymes are therefore considered potential drug targets.[2–4] Lysine specific demethylation 1 (LSD1) can remove the methyl group from a mono- or di-methylated lysine residue of histone H3 lysine 4 (H3K4), H3K9 or a non-histone protein.[5–7] The biological function of LSD1 is crucial, as LSD1 knockout in mice was found to be embryonic lethal, while conditional knockout blocked hematopoiesis. Overexpression of LSD1 was found in a broad range of cancers, including lung, prostate and breast cancers.[9–11] Recently, LSD1 has been reported to be a drug target for acute myeloid leukemia (AML).[12–14] AML is the major type of acute leukemia, showing a poor prognosis with 5-year survival rates being only 24.6%. Current treatments are mostly conventional chemotherapeutics, which non-selectively kill all rapidly dividing cells including normal cells in bone marrow and other organs. This causes severe toxicities and side effects that significantly limit the efficacy of these drugs. There is therefore a pressing need for new therapeutics to treat AML.
Aberrant histone modifications are often found in many types of cancer. LSD1, a demethylase for H3K4-Me2 or -Me1, has recently been found to be a drug target for AML. More structure activity relationship studies targeting LSD1 are therefore needed. In this study, a total of 35 cyclopropylamine and related compounds were synthesized and tested for their activities against recombinant human LSD1. The enzyme selectivity of selected compounds were also evaluated using related MAO-A and -B. SARs for these compounds include 1) a PCM or related R2 group that contains a basic amine functionality is critically important for both potent LSD1 inhibition and high selectivity; 2) while an ortho- or a meta-R1 substitution in the phenylcyclopropylamine is disfavored, the para-position may tolerate a broad range of substituents for potent LSD1 inhibition; 3) cyclopropylamine seems to be the best core structure for LSD1 inhibition, as compared to hydrazines and propargylamines; and 4) a novel series of cyclopropylimine compounds were found to be submicromolar inhibitors of LSD1. Docking studies were performed and provided possible binding models of compound 10 in LSD1 and MAO-A. Moreover, these modeling studies can rationalize the observed SARs and selectivity, particularly with respect to the critical role of the terminal basic amine group of R2 of these cyclopropylamine-containing compounds.