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Remodelin Sale

目录号 : GC11430

A NAT10 inhibitor that rescues laminopathies

Remodelin Chemical Structure

Cas No.:1622921-15-6

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5mg
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Cell experiment [1]:

Cell lines

Mouse melanoma cell line(B16F10)

Preparation Method

B16F10 cells were incubated with Remodelin and α- melanocyte - stimulating hormone (α-MSH) for 3 days. The harvested cells or media were centrifuged and the pellets were solubilized in sodium hydroxide for 1h. The melanin contents were measured using spectrophotometer at 475 nm wavelength (OD475).

Reaction Conditions

10, 20 µM Remodelin for 3 days.

Applications

α-MSH-mediated increase in the extracellular and intracellular melanin contents was significantly decreased upon treatment with 20 µM remodelin.Remodelin attenuates melanin synthesis by repressing MITF.

Animal experiment [2]:

Animal models

BALB/c nu/nu mice

Preparation Method

AR-negative prostate Cancer Cells (PC-3 cells) were inoculated into the armpits of mice by subcutaneous injection. One week later, Remodelin injection was performed every two days for a total of 4 weeks. Tumor size was measured every two days. Tumors were excised from nude mice and weighed after 4 weeks.

Dosage form

2,20 mg/kg Remodelin , i.p.injection

Applications

Remodelin significantly reduced AR-negative prostate cancer tumor growth, and in the high-dose Remodelin group, xenograft tumor weight at the endpoint was also much smaller than that in the low-dose group.Remodelin suppresses the growth and tumorigenesis potential of prostate cancer cells.

References:

[1]. Oh TI, Lee YM, et al.Inhibition of NAT10 Suppresses Melanogenesis and Melanoma Growth by Attenuating Microphthalmia-Associated Transcription Factor (MITF) Expression. Int J Mol Sci. 2017 Sep 7;18(9):1924.

[2]. Ma N, Liu H, et al.Inhibition of N-Acetyltransferase 10 Suppresses the Progression of Prostate Cancer through Regulation of DNA Replication. Int J Mol Sci. 2022 Jun 12;23(12):6573.

产品描述

Remodelin is a small molecule inhibitor of N-acetyltransferase 10 (NAT10).Dysregulation of N-acetyltransferase 10 (NAT10) is associated with the development of many types of tumors[1].

Combined remodelin and doxorubicin treatment reduced cell viability significantly more compared to cells treated with doxorubicin alone. EDU assays confirmed that both doxorubicin and remodelin decreased breast cancer cell proliferation more compared to cells treated with doxorubicin alone, suggesting remodelin attenuates doxorubicin resistance in breast cancer cells (MDA-MB-231)[2]

Remodelin was given daily by intragastric administration for 4 weeks. PDX model tumour volume was recorded and TGI was calculated. As a result, Remodelin significantly inhibited the growth of HNSCC PDXs in vivo[3]

The treatment of Remodelin could suppress the growth of cancer cells but not induce apoptosis, that Remodelin has little cytotoxicity. Remodelin significantly reduced AR-negative prostate cancer tumor growth. The anti-neoplastic effects of Remodelin through NAT10 inhibition should be credited to the slowing down of DNA replication, which could consequently attenuate replication stress-associated genomic instability, and ultimately delay the progression of prostate cancer[4]

References:
[1]. Ma R, Chen J, et al. Up regulation of NAT10 promotes metastasis of hepatocellular carcinoma cells through epithelial-to-mesenchymal transition.
[2]. Wu J, Zhu H, et al. Inhibition of N-acetyltransferase 10 using remodelin attenuates doxorubicin resistance by reversing the epithelial-mesenchymal transition in breast cancer. Am J Transl Res. 2018 Jan 15;10(1):256-264.
[3]. Tao W, Tian G, et al. NAT10 as a potential prognostic biomarker and therapeutic target for HNSCC. Cancer Cell Int. 2021 Aug 6;21(1):413.
[4]. Ma N, Liu H, et al.Inhibition of N-Acetyltransferase 10 Suppresses the Progression of Prostate Cancer through Regulation of DNA Replication. Int J Mol Sci. 2022 Jun 12;23(12):6573.

Remodelin 是 N-乙酰转移酶 10 (NAT10) 的小分子抑制剂。N-乙酰转移酶 10 (NAT10) 的失调与多种肿瘤的发生有关[1]

与单独使用多柔比星处理的细胞相比,重塑素和多柔比星联合处理显着降低了细胞活力。 EDU 测定证实,与单独使用阿霉素处理的细胞相比,多柔比星和重塑素都能更有效地降低乳腺癌细胞增殖,这表明重塑素可减弱乳腺癌细胞中的多柔比星耐药性 (MDA-MB-231)[2]

Remodelin 每天通过胃内给药给药,持续 4 周。记录PDX模型肿瘤体积并计算TGI。因此,Remodelin 在体内显着抑制 HNSCC PDXs 的生长[3]

Remodelin治疗可抑制癌细胞的生长但不诱导细胞凋亡,即Remodelin的细胞毒性很小。 Remodelin 显着降低了 AR 阴性前列腺癌肿瘤的生长。 Remodelin 通过抑制 NAT10 的抗肿瘤作用应归功于 DNA 复制的减慢,从而减弱复制应激相关的基因组不稳定性,并最终延缓前列腺癌的进展[4]

Chemical Properties

Cas No. 1622921-15-6 SDF
化学名 4-[2-(2-cyclopentylidenehydrazinyl)-1,3-thiazol-4-yl]benzonitrile;hydrobromide
Canonical SMILES C1CCC(=NNC2=NC(=CS2)C3=CC=C(C=C3)C#N)C1.Br
分子式 C15H15BrN4S 分子量 363.28
溶解度 ≥ 36.3mg/mL in DMSO 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 2.7527 mL 13.7635 mL 27.527 mL
5 mM 0.5505 mL 2.7527 mL 5.5054 mL
10 mM 0.2753 mL 1.3763 mL 2.7527 mL
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Research Update

Remodelin, a N-acetyltransferase 10 (NAT10) inhibitor, alters mitochondrial lipid metabolism in cancer cells

Remodelin is a small molecule inhibitor of N-acetyltransferase 10 (NAT10), reported to reverse the effect of cancer conditions such as epithelial to mesenchymal transition, hypoxia, and drug resistance. We analysed RNA seq data of siNAT10 and found many metabolic pathways were altered, this made us perform unbiased metabolic analysis. Here we performed untargeted metabolomics in Remodelin treated cancer cells using high-performance liquid chromatography-tandem mass spectrometry. Statistical analysis revealed a total number of 138 of which 52 metabolites were significantly modified in Remodelin treated cells. Among the most significantly altered metabolites, we identified metabolites related with mitochondrial fatty acid elongation (MFAE) and mitochondrial beta-oxidation such as lauroyl-CoA, cholesterol, triglycerides, (S)-3-hydroxyhexadecanoyl-CoA, and NAD+ . Furthermore, assessment showed alteration in expression of Enoyl-CoA hydratase, short chain 1, mitochondrial (ECHS1), and Mitochondrial trans-2-enoyl-CoA reductase (MECR) genes, associated with MFAE pathway. We also found statistically significant decrease in total cholesterol and triglycerides in Remodelin treated cancer cells. Overall, our results showed that Remodelin alters mitochondrial fatty acid metabolism and lipid accumulation in cancer cells. Finally, we validated these results in NAT10 knockdown cancer cells and found that NAT10 reduction results in alteration in gene expression associated with mitochondrial fatty acid metabolism, clearly suggesting the possible role of NAT10 in maintaining mitochondrial fatty acid metabolism.

Remodelin Is a Cryptic Assay Interference Chemotype That Does Not Inhibit NAT10-Dependent Cytidine Acetylation

Remodelin is a putative small molecule inhibitor of the RNA acetyltransferase NAT10 which has shown preclinical efficacy in models of the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS). Here we evaluate remodelin's assay interference characteristics and effects on NAT10-catalyzed RNA cytidine acetylation. We find the remodelin chemotype constitutes a cryptic assay interference compound, which does not react with small molecule thiols but demonstrates protein reactivity in ALARM NMR and proteome-wide affinity profiling assays. Biophysical analyses find no direct evidence for interaction of remodelin with the NAT10 acetyltransferase active site. Cellular studies verify that N4-acetylcytidine (ac4C) is a nonredundant target of NAT10 activity in human cell lines and find that this RNA modification is not affected by remodelin treatment in several orthogonal assays. These studies display the potential for remodelin's chemotype to interact with multiple protein targets in cells and indicate remodelin should not be applied as a specific chemical inhibitor of NAT10-catalyzed RNA acetylation.

Chemical inhibition of NAT10 corrects defects of laminopathic cells

Down-regulation and mutations of the nuclear-architecture proteins lamin A and C cause misshapen nuclei and altered chromatin organization associated with cancer and laminopathies, including the premature-aging disease Hutchinson-Gilford progeria syndrome (HGPS). Here, we identified the small molecule "Remodelin" that improved nuclear architecture, chromatin organization, and fitness of both human lamin A/C-depleted cells and HGPS-derived patient cells and decreased markers of DNA damage in these cells. Using a combination of chemical, cellular, and genetic approaches, we identified the acetyl-transferase protein NAT10 as the target of Remodelin that mediated nuclear shape rescue in laminopathic cells via microtubule reorganization. These findings provide insights into how NAT10 affects nuclear architecture and suggest alternative strategies for treating laminopathies and aging.

Remodelin, an inhibitor of NAT10, could suppress hypoxia-induced or constitutional expression of HIFs in cells

Hypoxia-inducible factors (HIFs) are key mediators expressed under hypoxic condition and involved in many kinds of disease such as cancer and abnormal angiogenesis. Thus, development of their inhibitor has been extensively explored. Here, we describe a finding that Remodelin, a specific inhibitor of NAT10, could also inhibit the expression of HIFs. The presence of Remodelin could suppress the elevated level of HIF-1α protein and its nuclear translocation induced by either treatment of cobalt chloride (CoCl2) or hypoxia in dose or time-dependent way. More importantly, Remodelin could also inhibit the constitutional expression of HIF-1α and HIF-2α in VHL mutant 786-0 cells. With using of cells with depletion of NAT10 by shRNA or Crispr-Cas9 edited, we further demonstrated that inhibition of HIFs by Remodelin should need NAT10 activity. In biological analysis, the treatment of cultured HUVECs with Remodelin could inhibit in vitro cell migration and invasion and tube-formation. Our investigation implied that Remodelin could be a new potential inhibitor of HIFs for using in angiogenesis targeting therapy in either cancers or inflammatory diseases.

NAT10 as a potential prognostic biomarker and therapeutic target for HNSCC

Background: Increasing evidence has demonstrated the critical roles of mRNA modification regulators on multiple types of cancers. However, it is still poorly known about the prognostic and therapeutic value of mRNA modification regulators in HNSCC.
Methods: The gene expression profile of 36 mRNA modification regulators and their corresponding clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Stepwise regression in R with both directions was used to construct a model for the prognosis of HNSCC. Univariate Cox regression survival analysis was performed to identify the most significant risk gene. Gene set enrichment analysis (GSEA) was applied to determine the cancer-associated pathways with NAT10. Immunohistochemistry (IHC) staining was performed to evaluate the expression of NAT10 in formalin fixed paraffin-embedded (FFPE) samples of HNSCC. Univariate and multivariate Cox regression survival analysis performed to identify the independent risk factors associated with the OS of patients with HNSCC. HNSCC cell lines (Cal-27, FaDu, and Detroit-562) were transfected with short interfering RNA (siRNA) targeting NAT10 or treated with Remodelin, a small-molecule inhibitor of NAT10. Knockdown efficiency of siRNA was assessed by quantitative real-time PCR (qRT-PCR) and western blotting. In addition, CCK-8 assay, scratch assay and transwell assay were used to examine the proliferation, migration, and invasion abilities of the three HNSCC cell lines after NAT10 was inhibited genetically and pharmaceutically. Cell cycle and cell apoptosis assays were performed by flow cytometry. Finally, the therapeutic value of Remodelin in HNSCC was evaluated via a patient-derived xenograft (PDX) model. The statistical analysis was performed with SPSS 23.0.
Results: A risk prediction model containing 10 mRNA modification regulators was constructed and showed prognostic value in HNSCC. NAT10 was further identified as a key risk gene and independent prognostic factor in TCGA HNSCC dataset. The GSEA analysis suggested that high NAT10 expression was associated with MYC, E2F, G2M checkpoint, mTORC1, DNA repair and oxidative phosphorylation pathways. NAT10 protein expression was significantly up-regulated in tumour cells compared to normal epithelial cells in FFPE samples and increased NAT10 protein expression was correlated with poor overall survival of 267 HNSCC patients. Genetic depletion of NAT10 using siRNA or chemical inhibition of NAT10 using Remodelin resulted in reduced cell proliferation, migration and invasion abilities in Cal-27, FaDu and Detroit-562 cells. Knockdown of NAT10 using siRNA significantly increased cell cycle arrest in S/G2-phase. Remodelin significantly inhibited tumour growth and tumour cell proliferation in the PDX model of HNSCC.
Conclusions: NAT10 could be a potential prognostic marker and a therapeutic target for HNSCC.