Structure-activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures

Shannon Lyn Nowotarski, Boobalan Pachaiyappan, Steven L. Holshouser, Craig J. Kutz, Youxuan Li, Yi Huang, Shiv K. Sharma, Robert A. Casero, Patrick M. Woster

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Methylation at specific histone lysine residues is a critical post-translational modification that alters chromatin architecture, and dysregulated lysine methylation/demethylation is associated with the silencing of tumor suppressor genes. The enzyme lysine-specific demethylase 1 (LSD1) complexed to specific transcription factors catalyzes the oxidative demethylation of mono- and dimethyllysine 4 of histone H3 (H3K4me and H3K4me2, respectively). We have previously reported potent (bis)urea and (bis)thiourea LSD1 inhibitors that increase cellular levels of H3K4me and H3K4me2, promote the re-expression of silenced tumor suppressor genes and suppress tumor growth in vitro. Here we report the design additional (bis)urea and (bis)thiourea LSD1 inhibitors that feature 3-5-3 or 3-6-3 carbon backbone architectures. Three of these compounds displayed single-digit IC50 values in a recombinant LSD1 assay. In addition, compound 6d exhibited an IC50 of 4.2 μM against the Calu-6 human lung adenocarcinoma line, and 4.8 μM against the MCF7 breast tumor cell line, in an MTS cell viability assay. Following treatment with 6b-6d, Calu-6 cells exhibited a significant increase in the mRNA expression for the silenced tumor suppressor genes SFRP2, HCAD and p16, and modest increases in GATA4 message. The compounds described in this paper represent the most potent epigenetic modulators in this series, and have potential for use as antitumor agents.

Original languageEnglish (US)
Pages (from-to)1601-1612
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number7
DOIs
StatePublished - Apr 1 2015

Fingerprint

Lysine
Carbon
Tumors
Tumor Suppressor Genes
Thiourea
Methylation
Genes
Histones
Inhibitory Concentration 50
Urea
Assays
Cells
Post Translational Protein Processing
Tumor Cell Line
Epigenomics
Antineoplastic Agents
Modulators
Chromatin
Cell Survival
Transcription Factors

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Nowotarski, Shannon Lyn ; Pachaiyappan, Boobalan ; Holshouser, Steven L. ; Kutz, Craig J. ; Li, Youxuan ; Huang, Yi ; Sharma, Shiv K. ; Casero, Robert A. ; Woster, Patrick M. / Structure-activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures. In: Bioorganic and Medicinal Chemistry. 2015 ; Vol. 23, No. 7. pp. 1601-1612.
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Structure-activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures. / Nowotarski, Shannon Lyn; Pachaiyappan, Boobalan; Holshouser, Steven L.; Kutz, Craig J.; Li, Youxuan; Huang, Yi; Sharma, Shiv K.; Casero, Robert A.; Woster, Patrick M.

In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 7, 01.04.2015, p. 1601-1612.

Research output: Contribution to journalArticle

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AU - Nowotarski, Shannon Lyn

AU - Pachaiyappan, Boobalan

AU - Holshouser, Steven L.

AU - Kutz, Craig J.

AU - Li, Youxuan

AU - Huang, Yi

AU - Sharma, Shiv K.

AU - Casero, Robert A.

AU - Woster, Patrick M.

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AB - Methylation at specific histone lysine residues is a critical post-translational modification that alters chromatin architecture, and dysregulated lysine methylation/demethylation is associated with the silencing of tumor suppressor genes. The enzyme lysine-specific demethylase 1 (LSD1) complexed to specific transcription factors catalyzes the oxidative demethylation of mono- and dimethyllysine 4 of histone H3 (H3K4me and H3K4me2, respectively). We have previously reported potent (bis)urea and (bis)thiourea LSD1 inhibitors that increase cellular levels of H3K4me and H3K4me2, promote the re-expression of silenced tumor suppressor genes and suppress tumor growth in vitro. Here we report the design additional (bis)urea and (bis)thiourea LSD1 inhibitors that feature 3-5-3 or 3-6-3 carbon backbone architectures. Three of these compounds displayed single-digit IC50 values in a recombinant LSD1 assay. In addition, compound 6d exhibited an IC50 of 4.2 μM against the Calu-6 human lung adenocarcinoma line, and 4.8 μM against the MCF7 breast tumor cell line, in an MTS cell viability assay. Following treatment with 6b-6d, Calu-6 cells exhibited a significant increase in the mRNA expression for the silenced tumor suppressor genes SFRP2, HCAD and p16, and modest increases in GATA4 message. The compounds described in this paper represent the most potent epigenetic modulators in this series, and have potential for use as antitumor agents.

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