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

Bioorganic & Medicinal Chemistry
Shannon NowotarskiPatrick M Woster

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 4.2μM against the Calu-6 human lung adenocarcinoma line, and 4.8μM 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 ...Continue Reading

References

Mar 21, 2007·Biochemistry·Dawn M Z Schmidt, Dewey G McCafferty
Mar 25, 2010·International Journal of Cancer. Journal International Du Cancer·Shinya HayamiRyuji Hamamoto
Jan 8, 2013·MedChemComm·Shiv K SharmaPatrick M Woster
Aug 15, 2013·Molecular Cancer Therapeutics·Tracy Murray-StewartRobert A Casero

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Citations

Dec 29, 2015·Journal of Medicinal Chemistry·Tom E McAllisterChristopher J Schofield
Mar 12, 2016·Journal of Medicinal Chemistry·Bo WangPatrick M Woster
Jan 5, 2017·Cold Spring Harbor Perspectives in Medicine·Ashwini JambhekarYang Shi
Mar 25, 2017·Chemical Reviews·H Ümit KaniskanJian Jin
Sep 30, 2016·The Biochemical Journal·Tracy R Murray-StewartRobert A Casero
Mar 10, 2017·Epigenetics : Official Journal of the DNA Methylation Society·Hideaki Niwa, Takashi Umehara
Sep 6, 2018·Nature Reviews. Cancer·Robert A CaseroAnthony E Pegg
Jun 14, 2019·MedChemComm·Steven HolshouserPatrick M Woster
Jan 23, 2021·RSC Medicinal Chemistry·Samir Mehndiratta, Jing-Ping Liou
Feb 24, 2021·Journal of Medicinal Chemistry·Xing-Jie DaiHong-Min Liu
Jun 24, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Sarder ArifuzzamanRabeya Khatun
Feb 21, 2018·European Journal of Medicinal Chemistry·Isuru R Kumarasinghe, Patrick M Woster
May 5, 2021·European Journal of Medicinal Chemistry·Xiangyu ZhangMaosheng Cheng

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