Dual Inhibitors of LSD1 and Spermine Oxidase

Overview

Journal Medchemcomm

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2019 Jun 14

PMID 31191868

Citations 9

Authors

Steven Holshouser

Matthew Dunworth

Tracy Murray-Stewart

Yuri K Peterson

Pieter Burger

Joy KirkPatrick

Huan-Huan Chen

Robert A Casero Jr

Patrick M Woster

Affiliations

Soon will be listed here.

Abstract

We have previously described the synthesis and evaluation of 3,5-diamino-1,2,4-triazole analogues as inhibitors of the flavin-dependent histone demethylase LSD1. These compounds are potent inhibitors of LSD1 without activity against monoamine oxidases A and B, and promote the elevation of H3K4me2 levels in tumor cells . We now report that the cytotoxicity of these analogues in pancreatic tumor cells correlates with the overexpression of LSD1 in each tumor type. In addition, we show that a subset of these 3,5-diamino-1,2,4-triazole analogues inhibit a related flavin-dependent oxidase, the polyamine catabolic enzyme spermine oxidase (SMOX) .

Citing Articles

LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials.

Noce B, Di Bello E, Fioravanti R, Mai A Front Pharmacol. 2023; 14:1120911.

PMID: 36817147 PMC: 9932783. DOI: 10.3389/fphar.2023.1120911.

Modulation of histone H3K4 dimethylation by spermidine ameliorates motor neuron survival and neuropathology in a mouse model of ALS.

Choi S, Yousefian-Jazi A, Hyeon S, Nguyen P, Chu J, Kim S J Biomed Sci. 2022; 29(1):106.

PMID: 36536341 PMC: 9764677. DOI: 10.1186/s12929-022-00890-3.

Identification and Characterization of Novel Small-Molecule SMOX Inhibitors.

Furbish A, Alford A, Burger P, Peterson Y, Murray-Stewart T, Casero Jr R Med Sci (Basel). 2022; 10(3).

PMID: 36135832 PMC: 9504029. DOI: 10.3390/medsci10030047.

Structure of human spermine oxidase in complex with a highly selective allosteric inhibitor.

Diaz E, Adhikary S, Tepper A, Riley D, Ortiz-Meoz R, Krosky D Commun Biol. 2022; 5(1):787.

PMID: 35931745 PMC: 9355956. DOI: 10.1038/s42003-022-03735-9.

Histone lysine specific demethylase 1 inhibitors.

Mehndiratta S, Liou J RSC Med Chem. 2021; 11(9):969-981.

PMID: 33479691 PMC: 7513387. DOI: 10.1039/d0md00141d.

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