CMS121

CMS121 (CAS 1353224-53-9) is a synthetic quinoline derivative of the dietary flavonoid fisetin (3,7,3',4'-tetrahydroxyflavone), identified through a phenotypic screening cascade at the Salk Institute for Biological Studies as a potent inhibitor of oxytotic/ferroptotic neuronal cell death with nanomolar protective activity in glutamate toxicity and iodoacetic acid toxicity assays in the HT22 hippocampal cell line. The compound was selected from more than 160 synthetic fisetin derivatives prepared by Chiruta, Schubert, Dargusch, and Maher (Journal of Medicinal Chemistry, 2012) through a multitiered screening approach that evaluated neuroprotective potency, anti-inflammatory activity, and oral pharmacokinetic suitability. The molecular target of CMS121 was subsequently identified as fatty acid synthase (FASN), with dose-dependent enzymatic inhibition demonstrated in cell lysate assays (Ates, Goldberg, Currais, and Maher, Redox Biology, 2020). Downstream of FASN inhibition, CMS121 engages the AMP-activated protein kinase/acetyl-CoA carboxylase 1 (AMPK/ACC1) axis, elevating intracellular acetyl-CoA levels and promoting histone H3 lysine 9 acetylation, a modification linked to memory enhancement in the senescence-accelerated mouse prone 8 (SAMP8) model (Currais et al., eLife, 2019). The anti-ferroptotic mechanism operates through reduction of polyunsaturated fatty acid substrates available for lipid peroxidation, thereby decreasing 4-hydroxynonenal protein adduct accumulation and suppressing downstream neuroinflammatory cascades including inducible nitric oxide synthase, cyclooxygenase-2, and tumor necrosis factor-alpha expression in activated microglia. Preclinical efficacy has been demonstrated across multiple disease models: in APPswe/PS1deltaE9 double transgenic Alzheimer's disease mice, dietary CMS121 at 400 parts per million (approximately 34 mg/kg) for three months beginning at nine months of age normalized spatial memory, contextual fear conditioning, and hippocampal lipid peroxidation markers to wild-type levels; in SAMP8 accelerated aging mice, four months of treatment preserved cognition and reduced transcriptional markers of brain aging; in R6/2 and YAC128 Huntington's disease models, CMS121 slowed motor dysfunction and extended median lifespan by up to 17 percent; and in db/db leptin receptor deficient mice and wild-type C57BL/6 mice, the compound ameliorated metabolic dysfunction, reduced adiposity, and improved hepatic and renal biomarkers. The compound was advanced to a first-in-human Phase 1 clinical trial (NCT05318040) by Virogenics, Inc. in collaboration with the National Institute on Aging, conducted at Celerion (Lincoln, Nebraska) in 2022. Single ascending doses up to 1800 mg and multiple ascending doses up to 900 mg in the published literature for seven days were generally well tolerated in approximately 88 healthy volunteers, with the majority of treatment-emergent adverse events mild in severity. Pharmacokinetics were dose-proportional or slightly greater than dose-proportional; the CMS121-C2 metabolite was the predominant circulating species; urinary excretion was minimal; systemic exposure was approximately 50 percent higher in the fed state; and elderly subjects exhibited higher exposures and longer terminal elimination half-lives than young adults (Maher, Christopher, Evans, and Raschke, medRxiv, 2025, preprint). This monograph reviews the chemistry and structural relationship to fisetin; the FASN/ACC1/AMPK molecular pharmacology; the preclinical evidence base across Alzheimer's disease, Huntington's disease, aging, and metabolic models; the Phase 1 human pharmacokinetic and safety data; sourcing and handling considerations for research applications; and a comparative assessment of five related compounds (fisetin, J147, CAD031, denifanstat, and ferrostatin-1) against CMS121 on five competency standards. The compound has not received regulatory approval for any therapeutic indication. It is positioned as a research-grade geroneuroprotector for investigational use.