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Purity: ≥98%
CMS-121 (CMS121) is a novel and potent fisetin-based quinolone derivative acting as an orally active acetyl-CoA carboxylase 1 (ACC1) inhibitor with anti-aging, neuroprotective, anti-inflammatory, antioxidative, and renoprotective activities. It is currently in the animal toxicology studies required for FDA approval to start clinical trials for AD treatment.
| Targets |
Acetyl-CoA carboxylase 1 (ACC1)[1]
ACC1 is phosphorylated at serine 79 more when treated with CMS-121 (1 µM; 4 hours; HT22 cells). Elevating acetyl-CoA in cells is possible with CMS-121 [1]. |
|---|---|
| ln Vitro |
ACC1 is phosphorylated at serine 79 more when treated with CMS-121 (1 µM; 4 hours; HT22 cells). Elevating acetyl-CoA in cells is possible with CMS-121 [1].
CMS121 (500 nM) protected HT22 mouse hippocampal neuronal cells from oxytosis (a form of programmed cell death induced by glutamate involving mitochondrial ROS). [1] CMS121 (1 μM) increased total acetyl-CoA levels in rat primary cortical neurons after 24-hour treatment. [1] CMS121 (1 μM) increased acetylation of histone H3 at lysine 9 (H3K9) in rat primary cortical neurons. [1] CMS121 (1 μM) increased phosphorylation of acetyl-CoA carboxylase 1 (ACC1) at serine 79 in rat primary cortical neurons and in HT22 cells. [1] CMS121 (1 μM) decreased levels of polyunsaturated fatty acids in primary neurons after 24-hour treatment. [1] In mouse hippocampal HT22 cells, CMS121 increased acetyl-CoA levels. [1] Network analysis integrating transcriptomic and metabolomic data from cultured, differentiated rat cortical neurons treated with CMS121 identified acetyl-CoA as a central regulated metabolite. [1] |
| ln Vivo |
When given to rapidly aging SAMP8 mice, CMS-121 (~20 mg/kg; oral dose; daily; for 4 months; female SAMP8 mice) lowers both cognitive decline and metabolic and transcriptional indicators of aging in the brain. Through controlling the metabolism of acetyl-coenzyme A (acetyl-CoA), CMS-121 maintains mitochondrial homeostasis[1].
In aged (13-month-old) senescence-accelerated prone 8 (SAMP8) mice (a model of accelerated aging and dementia), oral administration of CMS121 (400 ppm in diet, ~20 mg/kg/day for 4 months, starting at 9 months of age) prevented age-associated transcriptomic drift in the hippocampus, shifting the transcriptomic profile closer to that of younger (9-month-old) mice. [1] CMS121 treatment reduced cognitive decline in aged SAMP8 mice. It prevented age-associated increase in disinhibition behavior in the elevated plus maze and improved spatial learning during the reversal phase of the Barnes maze. [1] CMS121 specifically maintained the expression of mitochondrial-related genes (e.g., genes encoding electron transport chain complexes and ATP synthase) that were altered with aging in SAMP8 mouse hippocampus. [1] CMS121 modulated brain cortical metabolome in aged SAMP8 mice. It significantly restored the age-decreased level of acetyl-CoA and age-increased levels of α-ketoglutarate and succinate (TCA cycle metabolites) to levels similar to younger mice. It also increased levels of various acyl carnitines. [1] CMS121 increased phosphorylation of ACC1 in the brain cortex of SAMP8 mice. [1] CMS121 prevented the age-associated decrease in acetylation of histone H3 at lysine 9 (H3K9) in the cortex of SAMP8 mice. [1] CMS121 decreased levels of multiple long-chain fatty acids in the brains and plasma of aged SAMP8 mice. [1] CMS121 showed a partial suppression of age-related metabolic drift in the blood plasma of SAMP8 mice. [1] In old symptomatic APPswe/PSEN1dE9 transgenic Alzheimer's disease mouse model, CMS121 treatment increased acetylation of H3K9 in the brain. [1] |
| Cell Assay |
Western Blot Analysis[1]
Cell Types: HT22 cells Tested Concentrations: 1 µM Incubation Duration: 4 hrs (hours) Experimental Results: Increases the phosphorylation of ACC1 at serine 79. Oxytosis Protection Assay: Mouse hippocampal HT22 cells were used. Oxytosis was induced by glutamate, which inhibits cystine uptake, leading to glutathione depletion, mitochondrial ROS production, and cell death. Cell survival/protection was assessed after co-treatment with CMS121. [1] Acetyl-CoA Measurement: Acetyl-CoA levels were determined in protein-free lysates of primary neurons or HT22 cells treated with CMS121 using a commercial kit. Levels were normalized to total protein content. [1] Western Blotting: Treated cells (primary neurons or HT22) or brain tissue samples were lysed. Proteins were separated by electrophoresis, transferred to membranes, and probed with specific primary antibodies (e.g., phospho-ACC1, total ACC1, acetyl-H3K9, total H3). Detection was performed using horseradish peroxidase-conjugated secondary antibodies. [1] ACC1 Inhibition/Knockdown Validation: ACC1 activity was chemically inhibited using TOFA (5-(tetradecyloxy)-2-furoic acid) in HT22 cells. Alternatively, ACC1 expression was reduced using specific siRNA transfection in HT22 cells. Acetyl-CoA levels and cell survival during oxytosis were subsequently measured. [1] Ferroptosis Protection Assay: HT22 cells were subjected to ferroptosis induced by RSL3. Protection by CMS121 or ACC1 knockdown was assessed by measuring cell survival. [1] |
| Animal Protocol |
Animal/Disease Models: Female SAMP8 mice (9 months old)[1]
Doses: ~20 mg/kg/day Route of Administration: Oral administration; daily; for 4 months Experimental Results: decreased cognitive decline as well as metabolic and transcriptional markers of aging in the brain. SAMP8 Mouse Aging/Dementia Model: Female SAMP8 mice at 9 months of age were used. CMS121 was administered via diet at a concentration of 400 ppm (approximately 20 mg/kg/day) mixed into standard laboratory rodent chow. The treatment continued for 4 months until mice reached 13 months of age. A control group received vehicle diet. A baseline control group consisted of 9-month-old SAMP8 mice. Behavioral tests (elevated plus maze, Barnes maze) were conducted one month before sacrifice. Mice were then anesthetized, blood was collected via cardiac puncture, and after perfusion with PBS, brains were removed for dissection of cortex and hippocampus for subsequent biochemical, transcriptomic, and metabolomic analyses. [1] APPswe/PSEN1dE9 Transgenic AD Mouse Model: In a separate study, 10-month-old male transgenic and wild-type mice were fed a diet containing 400 ppm CMS121 for three months. Brain cortical tissue was collected for analysis. [1] |
| Toxicity/Toxicokinetics |
In a 4-month treatment study of aged SAMP8 mice, administration of CMS121 had no significant effect on body weight compared to mice fed a control diet. [1]
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| References | |
| Additional Infomation |
CMS-121 is a quinolone derivative and an orally potent inhibitor of acetyl-CoA carboxylase 1 (ACC1). CMS-121 protects HT22 cells from ischemic and oxidative damage. CMS-121 exhibits significant neuroprotective, anti-inflammatory, antioxidant, and renal protective activities.
CMS121 is a more potent derivative of the flavonol fisetone, retaining most of the biological properties of fisetone. [1] It was discovered through a screening trial based on a phenotypic drug discovery paradigm that mimics various aspects of age-related neurodegenerative diseases, including energy depletion and mitochondrial dysfunction. [1] Its mechanism of action is thought to be the inhibition of acetyl-CoA carboxylase 1 (ACC1), thereby increasing intracellular acetyl-CoA levels. This increase is associated with enhanced histone H3K9 acetylation (related to memory) and improved mitochondrial homeostasis, contributing to neuroprotection and improvement of age-related cognitive decline. [1] This study suggests that CMS121, by increasing acetyl-CoA levels in the brain, may provide an alternative to the ketogenic diet for treating mitochondrial dysfunction in aging and dementia. [1] |
| Molecular Formula |
C20H19NO3
|
|---|---|
| Molecular Weight |
321.369765520096
|
| Exact Mass |
321.136
|
| CAS # |
1353224-53-9
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| PubChem CID |
135741221
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| Appearance |
Light yellow to yellow solid powder
|
| LogP |
4.4
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
3
|
| Heavy Atom Count |
24
|
| Complexity |
412
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
O(C1C=C(C2C=CC(=C(C=2)O)O)N=C2C=CC=CC=12)C1CCCC1
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| InChi Key |
OMHNVUCFPJJLKD-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C20H19NO3/c22-18-10-9-13(11-19(18)23)17-12-20(24-14-5-1-2-6-14)15-7-3-4-8-16(15)21-17/h3-4,7-12,14,22-23H,1-2,5-6H2
|
| Chemical Name |
4-(4-(cyclopentyloxy)quinolin-2-yl)benzene-1,2-diol
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| Synonyms |
CMS-121, CMS 121, CMS121
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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 (~155.58 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.47 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 20.8 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: ≥ 2.08 mg/mL (6.47 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 20.8 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1117 mL | 15.5584 mL | 31.1168 mL | |
| 5 mM | 0.6223 mL | 3.1117 mL | 6.2234 mL | |
| 10 mM | 0.3112 mL | 1.5558 mL | 3.1117 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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