NVS-CECR2-1
(Synonyms: NVS-1) 目录号 : GC44477A potent and selective CECR2 inhibitor
Cas No.:1992047-61-6
Sample solution is provided at 25 µL, 10mM.
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- Purity: >99.00%
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NVS-CECR2-1 is a potent inhibitor of CECR2 (cat eye syndrome chromosome region, candidate 2), a component of chromatin complexes that regulate gene expression controlling development. It binds CECR2 with high affinity (IC50 = 0.047 µM by Alpha screen, Kd = 0.80 µM by ITC). NVS-CECR2-1 demonstrates no crossreactivity in a panel of 48 bromodomains and has no major activity in kinase, protease, and receptor panels. It shows robust activity in cells by FRAP assay, due to its slow off-rate, and has no acute toxicity. See the Structural Genomics Consortium (SGC) website for more information.
Cas No. | 1992047-61-6 | SDF | |
别名 | NVS-1 | ||
Canonical SMILES | O=S(C1=NC(NC2CC2)=CC(C3=CC(C=CN4C5CC(C)(C)NC(C)(C)C5)=C4C=C3)=N1)(CCC)=O | ||
分子式 | C27H37N5O2S | 分子量 | 495.7 |
溶解度 | DMSO: 0.3 mg/mL | 储存条件 | 4°C, protect from light |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.0173 mL | 10.0867 mL | 20.1735 mL |
5 mM | 0.4035 mL | 2.0173 mL | 4.0347 mL |
10 mM | 0.2017 mL | 1.0087 mL | 2.0173 mL |
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Cytotoxic activity of bromodomain inhibitor NVS-CECR2-1 on human cancer cells
Sci Rep 2020 Oct 1;10(1):16330.PMID:33004947DOI:10.1038/s41598-020-73500-7.
Bromodomain (BRD), a protein module that recognizes acetylated lysine residues on histones and other proteins, has recently emerged as a promising therapeutic target for human diseases such as cancer. While most of the studies have been focused on inhibitors against BRDs of the bromo- and extra-terminal domain (BET) family proteins, non-BET family BRD inhibitors remain largely unexplored. Here, we investigated a potential anticancer activity of the recently developed non-BET family BRD inhibitor NVS-CECR2-1 that targets the cat eye syndrome chromosome region, candidate 2 (CECR2). We show that NVS-CECR2-1 inhibits chromatin binding of CECR2 BRD and displaces CECR2 from chromatin within cells. NVS-CECR2-1 exhibits cytotoxic activity against various human cancer cells, killing SW48 colon cancer cells in particular with a submicromolar half maximum inhibition value mainly by inducing apoptosis. The sensitivity of the cancer cells to NVS-CECR2-1 is reduced by CECR2 depletion, suggesting that NVS-CECR2-1 exerts its activity by targeting CECR2. Interestingly, our data show that NVS-CECR2-1 also kills cancer cells by CECR2-independent mechanism. This study reports for the first time the cancer cell cytotoxic activity for NVS-CECR2-1 and provides a possibility of this BRD inhibitor to be developed as an anticancer therapeutic agent.
The repositioning of epigenetic probes/inhibitors identifies new anti-schistosomal lead compounds and chemotherapeutic targets
PLoS Negl Trop Dis 2019 Nov 15;13(11):e0007693.PMID:31730617DOI:10.1371/journal.pntd.0007693.
Background: Praziquantel represents the frontline chemotherapy used to treat schistosomiasis, a neglected tropical disease (NTD) caused by infection with macro-parasitic blood fluke schistosomes. While this drug is safe, its inability to kill all schistosome lifecycle stages within the human host often requires repeat treatments. This limitation, amongst others, has led to the search for novel anti-schistosome replacement or combinatorial chemotherapies. Here, we describe a repositioning strategy to assess the anthelmintic activity of epigenetic probes/inhibitors obtained from the Structural Genomics Consortium. Methodology/principle findings: Thirty-seven epigenetic probes/inhibitors targeting histone readers, writers and erasers were initially screened against Schistosoma mansoni schistosomula using the high-throughput Roboworm platform. At 10 μM, 14 of these 37 compounds (38%) negatively affected schistosomula motility and phenotype after 72 hours of continuous co-incubation. Subsequent dose-response titrations against schistosomula and adult worms revealed epigenetic probes targeting one reader (NVS-CECR2-1), one writer (LLY-507 and BAY-598) and one eraser (GSK-J4) to be particularly active. As LLY-507/BAY-598 (SMYD2 histone methyltransferase inhibitors) and GSK-J4 (a JMJD3 histone demethylase inhibitor) regulate an epigenetic process (protein methylation) known to be critical for schistosome development, further characterisation of these compounds/putative targets was performed. RNA interference (RNAi) of one putative LLY-507/BAY-598 S. mansoni target (Smp_000700) in adult worms replicated the compound-mediated motility and egg production defects. Furthermore, H3K36me2, a known product catalysed by SMYD2 activity, was also reduced by LLY-507 (25%), BAY-598 (23%) and siSmp_000700 (15%) treatment of adult worms. Oviposition and packaging of vitelline cells into in vitro laid eggs was also significantly affected by GSK-J4 (putative cell permeable prodrug inhibitor of Smp_034000), but not by the related structural analogue GSK-J1 (cell impermeable inhibitor). Conclusion/significance: Collectively, these results provide further support for the development of next-generation drugs targeting schistosome epigenetic pathway components. In particular, the progression of histone methylation/demethylation modulators presents a tractable strategy for anti-schistosomal control.