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| Targets |
HuR[1]
CMLD-2 targets Human antigen R (HuR), an RNA-binding protein that regulates the stability and translation of target mRNAs. The compound competitively binds HuR protein with a Ki of 350 nM and disrupts its interaction with adenine-uridine-rich element (ARE) mRNA targets. By blocking HuR binding to ARE-containing mRNAs, CMLD-2 decreases the stability and protein levels of HuR-regulated targets such as Bcl2 and p27. The compound also inhibits the Wnt signaling pathway. |
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| ln Vitro |
CMLD-2 (1-75 μM; 24-72 h) suppresses the viability of thyroid cancer cells [2]. In H1299 and A549 cells, CMLD-2 (20–30 μM; 24-48 h) activates caspases and causes apoptotic cell death [3]. In H1299 and A549 cells, CMLD-2 (30 μM; 24-48 hours) causes mitochondrial disruption and G1 cell cycle arrest [3]. In H1299 cells, CMLD-2 (30 μM; 24-48 hours) decreases HuR and HuR-regulated mRNA and protein expression [3]. The directional migratory capacity of SW1736, 8505C, BCPAP, and K1 cells is decreased by CMLD-2 (35 μM; 72 hours). MAD2 mRNA levels in SW1736, 8505C, BCPAP, and K1 cells can be markedly decreased by CMLD-2 [2].
In vitro studies demonstrate that CMLD-2 (1-75 μM; 24-72 h) inhibits thyroid cancer cell viability. The compound (20-30 μM; 24-48 h) activates caspases and induces apoptotic cell death in H1299 and A549 NSCLC cells. CMLD-2 causes G1 phase cell-cycle arrest and induces apoptosis in NSCLC cells. It decreases HuR mRNA and the mRNAs of HuR-regulated proteins including Bcl2 and p27. The compound displays cytotoxic selectivity on cancer cells and blocks HuR protein bound to MsI1 and XIAP mRNAs. |
| ln Vivo |
CMLD-2 induces apoptosis and exhibits antitumor activity in different cancer cell lines including colon, pancreatic, thyroid, and lung cancer. The compound causes G1 phase cell-cycle arrest in cancer cells. In vivo, CMLD-2 has demonstrated antitumor activity in various cancer models. The compound's mechanism involves disrupting HuR-mRNA interactions, leading to decreased expression of HuR-regulated proteins and inhibition of the Wnt signaling pathway.
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| Enzyme Assay |
The binding of CMLD-2 to HuR can be assessed using surface plasmon resonance (SPR) or fluorescence polarization assays. In a typical assay, recombinant HuR protein is incubated with fluorescently labeled ARE-containing RNA and varying concentrations of CMLD-2. The displacement of the RNA probe is measured, and the Ki (350 nM) is calculated. The specificity of CMLD-2 for HuR over other RNA-binding proteins can be confirmed using similar assays with different targets.
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| Cell Assay |
Cell Viability Assay[2]
Cell Types: SW1736, 8505C, BCPAP and K1 cells Tested Concentrations: 1, 5, 10, 25, 35, 50, 75 μM Incubation Duration: 24, 48, 72 hrs (hours) Experimental Results: decreased the viability of all the four cell lines when used at 35, 50 and 75 μM concentration and at different time points. Apoptosis Analysis[3] Cell Types: H1299, A549, H1975, HCC827, MRC-9 and CCD16 cells Tested Concentrations: 20, 30 μM Incubation Duration: 24, 48 hrs (hours) Experimental Results: Marked activated the caspase-9 and -3 in lung tumor cells. Induce the cleavage of PARP in lung tumor cells. Dramatically increased the annexin-V-positive staining in lung tumor cells. Cell Cycle Analysis[3] Cell Types: H1299, A549, MRC-9 and CCD16 cells Tested Concentrations: 30 μM Incubation Duration: 24, 48 hrs (hours) Experimental Results: Induced greater G1 phase cell cycle arrest in H1299 and A549 cells than in MRC-9 and CCD16 cells. Western Blot Analysis[3] Cell Types: H1299, A549, H1975, HCC827, CCD16 and MRC-9 cells Tested Concentrations: 20, 30 μM Incubation Duration: 24, 48 hrs (hours) Experimental Results: Diminished protei The cellular activity of CMLD-2 is assessed using various cancer cell lines including colon, pancreatic, thyroid, and lung cancer cells. Cells are treated with escalating concentrations of CMLD-2 (1-75 μM; 24-72 h). Cell viability is measured using MTT or CellTiter-Glo assays. Apoptosis is assessed by measuring caspase activation, annexin V/propidium iodide staining, or detecting cleaved PARP. Cell cycle analysis is performed using propidium iodide staining followed by flow cytometry. HuR target mRNA and protein levels are measured by qPCR and Western blotting. |
| Animal Protocol |
CMLD-2 has been evaluated in animal models of cancer, including colon, pancreatic, thyroid, and lung cancer models. In these studies, the compound is administered at various doses and schedules. Tumor volumes are measured. The compound induces apoptosis and exhibits antitumor activity. The mechanism involves disrupting HuR-mRNA interactions and inhibiting the Wnt signaling pathway.
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| ADME/Pharmacokinetics |
No detailed pharmacokinetic data has been published for CMLD-2. The compound has a molecular weight of 513.59 g/mol and a molecular formula of C31H31NO6. It is soluble in DMSO at 10 mM. The compound has a density of 1.2±0.1 g/cm³ and a boiling point of 741.3±60.0 °C. Further studies would be needed to characterize its absorption, distribution, metabolism, and excretion properties, including oral bioavailability, plasma protein binding, clearance, and half-life.
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| Toxicity/Toxicokinetics |
No detailed toxicity data has been published for CMLD-2. The compound displays cytotoxic selectivity on cancer cells. As a HuR inhibitor, it may have on-target toxicity in normal tissues that depend on HuR function. Comprehensive toxicology studies would be required to evaluate its safety profile for potential therapeutic development. The compound is intended for research use only.
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| References |
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| Additional Infomation |
Hu antigen R (HuR) inhibitors
CMLD-2 (CAS# 958843-91-9) is a small molecule disruptor of the HuR-mRNA interaction with a Ki of 350 nM. The compound competitively binds HuR protein and disrupts its interaction with ARE mRNA targets. It causes G1 phase cell-cycle arrest and induces apoptosis in NSCLC cells. CMLD-2 displays antitumor activity in colon, pancreatic, thyroid, and lung cancer cell lines. The molecular formula is C31H31NO6 and molecular weight is 513.59 g/mol. The compound also inhibits the Wnt signaling pathway. |
| Molecular Formula |
C31H31NO6
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|---|---|
| Molecular Weight |
513.58
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| Exact Mass |
513.215
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| Elemental Analysis |
C, 72.50; H, 6.08; N, 2.73; O, 18.69
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| CAS # |
958843-91-9
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| PubChem CID |
16746438
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
741.3±60.0 °C at 760 mmHg
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| Flash Point |
402.1±32.9 °C
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| Vapour Pressure |
0.0±2.4 mmHg at 25°C
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| Index of Refraction |
1.606
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| LogP |
5.59
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
38
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| Complexity |
839
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| Defined Atom Stereocenter Count |
0
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| SMILES |
COC1=CC=C(C=C1)C(CC(=O)N2CCCC2)C3=C(C=C(C4=C3OC(=O)C=C4C5=CC=CC=C5)OC)OC
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| InChi Key |
PROGRNRRJJYCNX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C31H31NO6/c1-35-22-13-11-21(12-14-22)23(17-27(33)32-15-7-8-16-32)29-25(36-2)19-26(37-3)30-24(18-28(34)38-31(29)30)20-9-5-4-6-10-20/h4-6,9-14,18-19,23H,7-8,15-17H2,1-3H3
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| Chemical Name |
5,7-dimethoxy-8-(1-(4-methoxyphenyl)-3-oxo-3-(pyrrolidin-1-yl)propyl)-4-phenyl-2H-chromen-2-one
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| Synonyms |
958843-91-9; CMLD-2; MLS000879470; SMR000465530; CMLD2; CMLD 2
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : 50 mg/mL (97.36 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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