Dual inhibitors of LSD1 and spermine oxidase

Steven Holshouser; Matthew Dunworth; Tracy Murray-Stewart; Yuri K. Peterson; Pieter Burger; Joy Kirkpatrick; Huan Huan Chen; Robert A. Casero; Patrick M. Woster

doi:10.1039/c8md00610e

Dual inhibitors of LSD1 and spermine oxidase

Steven Holshouser, Matthew Dunworth, Tracy Murray-Stewart, Yuri K. Peterson, Pieter Burger, Joy Kirkpatrick, Huan Huan Chen, Robert A. Casero, Patrick M. Woster

School of Medicine

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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 in vitro. 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) in vitro.

Original language	English (US)
Pages (from-to)	778-790
Number of pages	13
Journal	MedChemComm
Volume	10
Issue number	5
DOIs	https://doi.org/10.1039/c8md00610e
State	Published - 2019

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Pharmaceutical Science
Drug Discovery
Organic Chemistry

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title = "Dual inhibitors of LSD1 and spermine oxidase",

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 in vitro. 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) in vitro.",

author = "Steven Holshouser and Matthew Dunworth and Tracy Murray-Stewart and Peterson, {Yuri K.} and Pieter Burger and Joy Kirkpatrick and Chen, {Huan Huan} and Casero, {Robert A.} and Woster, {Patrick M.}",

note = "Funding Information: The research described in this manuscript was supported by National Institutes of Health grants 1 RO1 CA149095 (P. M. W.) and 1 RO1 CA204345 (R. A. C., P. M. W.), and the Samuel Waxman Cancer Research Foundation (R. A. C.). We are grateful to the MUSC Hollings Cancer Center Biorepository and Tissue Analysis Shared Resource for providing pancreatic tissue slices. Publisher Copyright: {\textcopyright} 2019 The Royal Society of Chemistry.",

year = "2019",

doi = "10.1039/c8md00610e",

language = "English (US)",

volume = "10",

pages = "778--790",

journal = "MedChemComm",

issn = "2040-2503",

publisher = "Royal Society of Chemistry",

number = "5",

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TY - JOUR

T1 - Dual inhibitors of LSD1 and spermine oxidase

AU - Holshouser, Steven

AU - Dunworth, Matthew

AU - Murray-Stewart, Tracy

AU - Peterson, Yuri K.

AU - Burger, Pieter

AU - Kirkpatrick, Joy

AU - Chen, Huan Huan

AU - Casero, Robert A.

AU - Woster, Patrick M.

N1 - Funding Information: The research described in this manuscript was supported by National Institutes of Health grants 1 RO1 CA149095 (P. M. W.) and 1 RO1 CA204345 (R. A. C., P. M. W.), and the Samuel Waxman Cancer Research Foundation (R. A. C.). We are grateful to the MUSC Hollings Cancer Center Biorepository and Tissue Analysis Shared Resource for providing pancreatic tissue slices. Publisher Copyright: © 2019 The Royal Society of Chemistry.

PY - 2019

Y1 - 2019

N2 - 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 in vitro. 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) in vitro.

AB - 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 in vitro. 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) in vitro.

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SP - 778

EP - 790

JO - MedChemComm

JF - MedChemComm

IS - 5

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Dual inhibitors of LSD1 and spermine oxidase

Abstract

ASJC Scopus subject areas

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