Synthesis and biological evaluation of novel (E)-N′-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides as potent LSD1 inhibitors

Zhou, Yang; Li, Yan; Wang, Wenjing; Xiang, Ping; Luo, Xinmei; Yang, Li; Yang, Shengyong; Zhao, Yinglan

doi:10.1016/j.bmcl.2015.06.054

Cited by 35 publications

(35 citation statements)

References 15 publications

(13 reference statements)

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“…A sterically constrained derivative of HCI-2509, compound 5n, inhibited the growth of multiple cancer cell lines in culture more potently than HCI-2509 did (Fig. 3) (Zhou et al 2015). Collectively, these studies suggest that compounds not already known to be MAOIs could have LSD1-specific inhibitory properties, and could be optimized for clinical use.…”

Section: Other Inhibitorsmentioning

confidence: 87%

Histone Lysine Demethylase Inhibitors

Jambhekar

Anastas

Shi

2016

Cold Spring Harb Perspect Med

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The dynamic regulation of covalent modifications to histones is essential for maintaining genomic integrity and cell identity and is often compromised in cancer. Aberrant expression of histone lysine demethylases has been documented in many types of blood and solid tumors, and thus demethylases represent promising therapeutic targets. Recent advances in high-throughput chemical screening, structure-based drug design, and structure-activity relationship studies have improved both the specificity and the in vivo efficacy of demethylase inhibitors. This review will briefly outline the connection between demethylases and cancer and will provide a comprehensive overview of the structure, specificity, and utility of currently available demethylase inhibitors. To date, a select group of demethylase inhibitors is being evaluated in clinical trials, and additional compounds may soon follow from the bench to the bedside.

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Section: Other Inhibitorsmentioning

confidence: 87%

Histone Lysine Demethylase Inhibitors

Jambhekar

Anastas

Shi

2016

Cold Spring Harb Perspect Med

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“…In 2016, Zhou and co-workers aimed to improve potency and synthesized constrained derivatives of compound 37 . 539 Among these derivatives, compound 38 ( Figure 40 ) was the most potent with an IC 50 of 1.4 ± 0.3 nM in a biochemical assay, which was about 10-fold more potent than compound 37 . Compound 38 inhibited the proliferation of cancer cell lines such as A549, H1299, A2780, HCT116, MCF-7, MDA-MB-231, and DU145 with an IC 50 < 1 μM.…”

Section: Histone Demethylasesmentioning

confidence: 98%

Inhibitors of Protein Methyltransferases and Demethylases

2017

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Post-translational modifications of histones by protein methyltransferases (PMTs) and histone demethylases (KDMs) play an important role in the regulation of gene expression and transcription and are implicated in cancer and many other diseases. Many of these enzymes also target various nonhistone proteins impacting numerous crucial biological pathways. Given their key biological functions and implications in human diseases, there has been a growing interest in assessing these enzymes as potential therapeutic targets. Consequently, discovering and developing inhibitors of these enzymes has become a very active and fast-growing research area over the past decade. In this review, we cover the discovery, characterization, and biological application of inhibitors of PMTs and KDMs with emphasis on key advancements in the field. We also discuss challenges, opportunities, and future directions in this emerging, exciting research field.

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“…Through the structure-based virtual screening of 13 million compounds, the Sharma group identified the N´-(1-phenylethylidene)-benzohydrazides as moderate LSD1 inhibitors [54], further optimizations led to the identification of SP-2509 (compound 5, IC 50 = 13 nM) as a reversible and noncompetitive LSD1 inhibitor. SP-2509 showed high selectivity to LSD1 over MAOs (IC 50 > 300 μM) and inhibited survival of a panel of cancer cells at low micromolar levels with minimal inhibition against Cytochrome P450 (CYPs) and hERG.. Based on the structure of SP-2509, the Zhao group designed a new series of analogs using the conformational constraint strategy [55]. Among this series, compound 6 (IC 50 = 1.7 nM) exhibited about eightfold increase in LSD1 inhibition, increased the methylation levels of H3K4me2 and H3K9me2 in A2780 cells and inhibited growth of LSD1 overexpressed cell lines at low micromolar levels.…”

Section: Glu 379mentioning

confidence: 99%

Advances Toward Lsd1 Inhibitors for Cancer Therapy

Zhang

2017

Future Med. Chem.

112

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LSD1 has become an important biologically validated epigenetic target for cancer therapy since its identification in 2004. LSD1 mediates many cellular signaling pathways and is involved in the initiation and development of cancers. Aberrant overexpression of LSD1 has been observed in different types of cancers, and inactivation by small molecules suppresses cancer cell differentiation, proliferation, invasion and migration. To date, a large number of LSD1 inhibitors have been reported, RG6016, GSK-2879552, INCB059872, IMG-7289 and CC-90011 are currently undergoing clinical assessment for the treatment of acute myeloid leukemia, small-cell lung cancer, etc. In this review, we briefly highlight recent advances of LSD1 inhibitors mainly covering the literatures from 2015 to 2017 and tentatively propose our perspectives on the design of new LSD1 inhibitors for cancer therapy.

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Synthesis and biological evaluation of novel (E)-N′-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides as potent LSD1 inhibitors

Cited by 35 publications

References 15 publications

Histone Lysine Demethylase Inhibitors

Histone Lysine Demethylase Inhibitors

Inhibitors of Protein Methyltransferases and Demethylases

Advances Toward Lsd1 Inhibitors for Cancer Therapy

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