Description
Summary Abstract
CMS-121 (4-(4-cyclopentyloxyquinolin-2-yl)benzene-1,2-diol; CAS 1353224-53-9) is a synthetic quinolone derivative of the natural flavonoid fisetin, developed at the Salk Institute for Biological Studies as an orally active neuroprotective compound. Its primary mechanism targets fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1), two enzymes central to de novo fatty acid synthesis, thereby limiting substrate availability for lipid peroxidation — a key driver of oxytosis/ferroptosis-mediated neuronal death. In transgenic Alzheimer’s disease (AD) mouse models, CMS-121 alleviated cognitive decline, reduced brain inflammation, modulated lipid metabolism, and preserved mitochondrial acetyl-CoA homeostasis. A Phase 1 clinical trial has been initiated to evaluate safety in humans. The compound also demonstrated partial efficacy in slowing motor and cognitive decline in a Huntington’s disease (HD) mouse model and improved metabolic parameters in a SAMP8 accelerated-aging model.
Clinical Indications
CMS-121 has been evaluated across several preclinical neurodegeneration and aging models:
- Alzheimer’s Disease Models: Alleviated cognitive loss and reduced lipid peroxidation and neuroinflammation in transgenic AD mice; identified FASN as a novel therapeutic target in AD pathophysiology.
- Age-Related Cognitive Decline: Improved cognitive function in SAMP8 accelerated-aging mice and mitigated obesity, hepatic steatosis, and metabolic dysregulation markers in aged animals.
- Neurodegenerative Motor Disease: Partially attenuated rotarod and open-field performance decline and maintained forelimb grip strength in an HD mouse model, with moderate non-significant lifespan extension at lower doses.
Contraindications
- Lipid Metabolism Studies: CMS-121 inhibits FASN and activates AMPK-mediated ACC1 phosphorylation, substantially reducing de novo fatty acid synthesis; in vitro models relying on intact lipogenesis require appropriate control conditions.
- Hepatic and Adipose Tissue Experiments: FASN downregulation in liver and increased ACC1 phosphorylation in adipose tissue have been observed systemically, requiring consideration in metabolic study designs.
- Gluconeogenesis Models: Decreased PEPCK and increased PFKFB3 observed in hepatic tissue suggest CMS-121 reduces gluconeogenesis and enhances aerobic glycolysis; metabolic flux experiments should account for these effects.
Mechanism of Action (MOA)
CMS-121 exerts neuroprotection through coordinated modulation of lipid metabolic pathways:
FASN Inhibition
CMS-121 directly inhibits fatty acid synthase (FASN), reducing de novo synthesis of long-chain saturated fatty acids. This limits the pool of polyunsaturated fatty acids (PUFAs) available for iron-catalyzed lipid peroxidation — the mechanistic hallmark of oxytosis/ferroptosis, the non-apoptotic cell death pathway implicated in AD neurodegeneration.
AMPK/ACC1 Axis
FASN inhibition is complemented by AMPK activation, which phosphorylates and inhibits acetyl-CoA carboxylase 1 (ACC1). This limits conversion of acetyl-CoA into malonyl-CoA (a rate-limiting step in fatty acid synthesis), elevating mitochondrial acetyl-CoA levels and promoting histone acetylation at key epigenetic sites — linking metabolic and transcriptional neuroprotection.
Mitochondrial Acetyl-CoA Preservation
By redirecting acetyl-CoA away from lipid synthesis and toward mitochondrial oxidative metabolism, CMS-121 maintains mitochondrial homeostasis under oxidative stress. This has been identified as a primary driver of its cognitive-protective effects in AD and aging models, confirmed through metabolomic integration of gene expression, metabolite, and protein data.
Anti-inflammatory and Antioxidant Effects
Independent of lipid-synthesis inhibition, CMS-121 reduces neuroinflammation in transgenic AD brains, consistent with its fisetin-class flavonoid ancestry. Free PUFA reduction in primary neurons and brain tissue correlates with decreased lipid peroxidation markers and microglial activation indices.
Key Features & Specifications
CMS-121 is supplied as an encapsulated compound for oral bioavailability studies in neurodegenerative disease research:
Chemical Analysis
| Property | Specification Reference Data |
|---|---|
| IUPAC Name | 4-[4-(Cyclopentyloxy)quinolin-2-yl]benzene-1,2-diol |
| CAS Number | 1353224-53-9 |
| Molecular Formula | C20H19NO3 |
| Molecular Weight | 321.37 g/mol |
| PubChem CID | Available via PubChem search (CMS-121) |
| Synonyms | CMS121; 4-(4-(cyclopentyloxy)-2-quinolinyl)-1,2-benzenediol |
| Form / Variation | Capsules (SKU C-048, $58.00) |
Storage, Safety, and Handling
Storage Protocol
Store capsules at −20 °C in a sealed, moisture-proof container. The compound demonstrates high solubility in DMSO (≥20 mg/mL) and DMF (≥30 mg/mL) for solution-based assays. Powdered material should be kept away from light and humidity to prevent catechol ring oxidation.
Handling & Compliance
Handle with standard laboratory PPE. CMS-121 has advanced to Phase 1 clinical evaluation but carries no approved therapeutic indication. Institutional review of applicable regulations is required for any in vivo or ex vivo research use. WADA classification has not been assigned; this compound is not a controlled substance under current schedules.