CMLD-2
目录号 : GC61567
CMLD-2是一种HuR-ARE相互作用的抑制剂。CMLD-2竞争性结合HuR蛋白，破坏其与富含腺嘌呤-尿苷元素(ARE)的mRNA靶标的相互作用(Ki=350nM)。CMLD-2可诱导凋亡并在结肠癌，胰腺癌，甲状腺癌和肺癌细胞系中表现出抗肿瘤活性。Hu抗原R(HuR)是一种RNA结合蛋白，可以调节靶标mRNA的稳定性和翻译。
Cas No.:958843-91-9
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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CMLD-2, an inhibitor of HuR-ARE interaction, competitively binds HuR protein disrupting its interaction with adenine-uridine rich elements (ARE)-containing mRNAs (Ki=350 nM). CMLD-2 induces apoptosis exhibits antitumor activity in different cancer cells as colon, pancreatic, thyroid and lung cancer cell lines. Hu antigen R (HuR) is an RNA binding protein, can regulate target mRNAs stability and translation[1][2].
CMLD-2 (1-75 μM; 24-72 h) inhibits thyroid cancer cell viability[2].CMLD-2 (20-30 μM; 24-48 h) activates caspases and induces apoptotic cell death in H1299 and A549 cells[3].CMLD-2 (30 μM; 24-48 h) induces G1 cell cycle arrest and mitochondrial perturbation in H1299 and A549 cell[3].CMLD-2 (30 μM; 24-48 h) reduces expression of HuR and HuR-regulated mRNAs and proteins in H1299 cells[3].CMLD-2 (35 μM; 72 h) decreases directional migration capability in SW1736, 8505C, BCPAP and K1 cells. CMLD-2 induces a strong decrease of MAD2 mRNA levels in SW1736, 8505C, BCPAP and K1 cells[2]. Cell Viability Assay[2] Cell Line: SW1736, 8505C, BCPAP and K1 cells
[1]. Wu X, et, al. Identification and validation of novel small molecule disruptors of HuR-mRNA interaction. ACS Chem Biol. 2015 Jun 19;10(6):1476-84. [2]. Allegri , et, al. The HuR CMLD-2 inhibitor exhibits antitumor effects via MAD2 downregulation in thyroid cancer cells. Sci Rep. 2019 May 14;9(1):7374. [3]. Muralidharan R, et, al. HuR-targeted small molecule inhibitor exhibits cytotoxicity towards human lung cancer cells. Sci Rep. 2017 Aug 30;7(1):9694.
| Cas No. | 958843-91-9 | SDF | |
| Canonical SMILES | O=C1C=C(C2=CC=CC=C2)C3=C(OC)C=C(OC)C(C(C4=CC=C(OC)C=C4)CC(N5CCCC5)=O)=C3O1 | ||
| 分子式 | C31H31NO6 | 分子量 | 513.58 |
| 溶解度 | DMSO: 50 mg/mL (97.36 mM) | 储存条件 | Store at -20°C |
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| 1 mM | 1.9471 mL | 9.7356 mL | 19.4712 mL |
| 5 mM | 0.3894 mL | 1.9471 mL | 3.8942 mL |
| 10 mM | 0.1947 mL | 0.9736 mL | 1.9471 mL |
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The HuR CMLD-2 inhibitor exhibits antitumor effects via MAD2 downregulation in thyroid cancer cells
Sci Rep 2019 May 14;9(1):7374.PMID:31089242DOI:10.1038/s41598-019-43894-0.
Hu antigen R (HuR) is indeed one of the most studied RNA-binding protein (RBP) since its fundamental role both in tumorigenesis and cancer progression. For this reason, downregulation in HuR protein levels or inhibition of HuR biological function are, nowadays, attractive goals in cancer research. Here, we examined the antitumor effects of CMLD-2 in four thyroid cancer cell lines (SW1736, 8505 C, BCPAP and K1). Indeed, CMLD-2 competitively binds HuR protein disrupting its interaction with RNA-targets. 35 μM CLMD-2 produced a significant downregulation in thyroid cancer cell viability, coupled to an increase in apoptosis. Moreover, CMLD-2 treatment hindered both migration and colony formation ability. MAD2 is a microtubules-associated protein known to be greatly overexpressed in cancer and correlating with tumor aggressiveness. Furthermore, MAD2 is known to be a HuR target. CMLD-2 treatment induced a strong MAD2 downregulation and rescue experiments depicted it as a key effector in HuR-mediated in cancer. Altogether, these data contributed to foster HuR inhibition as valid antineoplastic treatment in thyroid cancer, highlighting MAD2 as a novel therapeutic target.
HuR-targeted small molecule inhibitor exhibits cytotoxicity towards human lung cancer cells
Sci Rep 2017 Aug 30;7(1):9694.PMID:28855578DOI:10.1038/s41598-017-07787-4.
Human antigen (Hu) R is an RNA-binding protein whose overexpression in human cancer correlates with aggressive disease, drug resistance, and poor prognosis. HuR inhibition has profound anticancer activity. Pharmacologic inhibitors can overcome the limitations of genetic inhibition. In this study, we examined the antitumor activity of CMLD-2, a small-molecule inhibitor directed against HuR, using non-small cell lung cancer (NSCLC) as a model. CMLD-2 efficacy was tested in vitro using H1299, A549, HCC827, and H1975 NSCLC cells and MRC-9 and CCD-16 normal human fibroblasts. Treatment of NSCLC cells with CMLD-2 produced dose-dependent cytotoxicity, caused a G1 phase cell-cycle arrest and induced apoptosis. CMLD-2 decreased HuR mRNA and the mRNAs of HuR-regulated proteins (Bcl2 and p27) in tumor cells. Additionally, reduction in the expression of HuR, Bcl2, cyclin E, and Bcl-XL with increased expression of Bax and p27 in CMLD-2-treated NSCLC cells were observed. CMLD-2-treated normal cells, HuR-regulated mRNAs and proteins albeit showed some reduction were less compared to tumor cells. Finally, CMLD-2 treatment resulted in greater mitochondrial perturbation, activation of caspase-9 and -3 and cleavage of PARP in tumor cells compared to normal cells. Our proof-of concept study results demonstrate CMLD-2 represents a promising HuR-targeted therapeutic class that with further development could lead to advanced preclinical studied and ultimately for lung cancer treatment.
The RNA-Binding Protein HuR Is Integral to the Function of Nociceptors in Mice and Humans
J Neurosci 2022 Dec 7;42(49):9129-9141.PMID:PMC9761683DOI:10.1523/JNEUROSCI.1630-22.2022.
HuR is an RNA-binding protein implicated in RNA processing, stability, and translation. Previously, we examined protein synthesis in dorsal root ganglion (DRG) neurons treated with inflammatory mediators using ribosome profiling. We found that the HuR consensus binding element was enriched in transcripts with elevated translation. HuR is expressed in the soma of nociceptors and their axons. Pharmacologic inhibition of HuR with the small molecule CMLD-2 reduced the activity of mouse and human sensory neurons. Peripheral administration of CMLD-2 in the paw or genetic elimination of HuR from sensory neurons diminished behavioral responses associated with NGF- and IL-6-induced allodynia in male and female mice. Genetic disruption of HuR altered the proximity of mRNA decay factors near a key neurotrophic factor (TrkA). Collectively, the data suggest that HuR is required for local control of mRNA stability and reveals a new biological function for a broadly conserved post-transcriptional regulatory factor.SIGNIFICANCE STATEMENT Nociceptors undergo long-lived changes in excitability, which may contribute to chronic pain. Noxious cues that promote pain lead to rapid induction of protein synthesis. The underlying mechanisms that confer specificity to mRNA control in nociceptors are unclear. Here, we identify a conserved RNA-binding protein called HuR as a key regulatory factor in sensory neurons. Using a combination of genetics and pharmacology, we demonstrate that HuR is required for signaling in nociceptors. In doing so, we report an important mechanism of mRNA control in sensory neurons that ensures appropriate nociceptive responses to inflammatory mediators.
HuR-Targeted Inhibition Impairs Th2 Proinflammatory Responses in Asthmatic CD4+ T Cells
J Immunol 2022 Jan 1;208(1):38-48.PMID:34862257DOI:10.4049/jimmunol.2100635.
RNA-binding protein HuR (ELAVL1) is a master regulator of gene expression in human pathophysiology. Its dysregulation plays an important role in many diseases. We hypothesized that HuR plays an important role in Th2 inflammation in asthma in both mouse and human. To address this, we used a model of airway inflammation in a T cell-specific knockout mouse model, distal lck-Cre HuRfl/fl, as well as small molecule inhibitors in human peripheral blood-derived CD4+ T cells. Peripheral CD4+ T cells were isolated from 26 healthy control subjects and 45 asthmatics (36 type 2 high and 9 non-type 2 high, determined by blood eosinophil levels and fraction of exhaled NO). Our mouse data showed conditional ablation of HuR in T cell-abrogated Th2 differentiation, cytokine production, and lung inflammation. Studies using human T cells showed that HuR protein levels in CD4+ T cells were significantly higher in asthmatics compared with healthy control subjects. The expression and secretion of Th2 cytokines were significantly higher in asthmatics compared with control subjects. AMP-activated protein kinase activator treatment reduced the expression of several cytokines in both type 2 high and non-type 2 high asthma groups. However, the effects of CMLD-2 (a HuR-specific inhibitor) were more specific to endotype-defining cytokines in type 2 high asthmatics. Taken together, these data suggest that HuR plays a permissive role in both allergen and non-allergen-driven airway inflammation by regulating key genes, and that interfering with its function may be a novel method of asthma treatment.
MUC16 promotes triple-negative breast cancer lung metastasis by modulating RNA-binding protein ELAVL1/HUR
Breast Cancer Res 2023 Mar 14;25(1):25.PMID:36918912DOI:10.1186/s13058-023-01630-7.
Background: Triple-negative breast cancer (TNBC) is highly aggressive with an increased metastatic incidence compared to other breast cancer subtypes. However, due to the absence of clinically reliable biomarkers and targeted therapy in TNBC, outcomes are suboptimal. Hence, there is an urgent need to understand biological mechanisms that lead to identifying novel therapeutic targets for managing metastatic TNBC. Methods: The clinical significance of MUC16 and ELAVL1 or Hu antigen R (HuR) was examined using breast cancer TCGA data. Microarray was performed on MUC16 knockdown and scramble TNBC cells and MUC16-associated genes were identified using RNA immunoprecipitation and metastatic cDNA array. Metastatic properties of MUC16 were evaluated using tail vein experiment. MUC16 and HuR downstream pathways were confirmed by ectopic overexpression of MUC16-carboxyl-terminal (MUC16-Cter), HuR and cMyc as well as HuR inhibitors (MS-444 and CMLD-2) in TNBC cells. Results: MUC16 was highly expressed in TNBC and correlated with its target HuR. Depletion of MUC16 showed decreased invasion, migration, and colony formation abilities of human and mouse TNBC cells. Mice injected with MUC16 depleted cells were less likely to develop lung metastasis (P = 0.001). Notably, MUC16 and HuR were highly expressed in the lung tropic TNBC cells and lung metastases. Mechanistically, we identified cMyc as a HuR target in TNBC using RNA immunoprecipitation and metastatic cDNA array. Furthermore, MUC16 knockdown and pharmacological inhibition of HuR (MS-444 and CMLD-2) in TNBC cells showed a reduction in cMyc expression. MUC16-Cter or HuR overexpression models indicated MUC16/HuR/cMyc axis in TNBC cell migration. Conclusions: Our study identified MUC16 as a TNBC lung metastasis promoter that acts through HuR/cMyc axis. This study will form the basis of future studies to evaluate the targeting of both MUC16 and HuR in TNBC patients.