CMS-121

CMS-121 (also written CMS121) is a synthetic small molecule from the Salk Institute group of Pamela Maher, Antonio Currais and David Schubert, designed from the plant flavonoid fisetin. Rebuilding fisetin's core as a quinoline with a cyclopentyl ether gave compound 121, more than 400 times as potent as fisetin in an HT22 nerve cell death assay (Chiruta et al., 2012).

Those, the structure and the other names are from PubChem CID 135741221, whose formula matches the mass the 2012 paper reported for compound 121.

Published work on CMS-121 falls into six areas. Each summary below states the model used. Apart from one phase 1 study, the evidence is cell and animal data. Every mouse study described below includes authors from the Salk laboratory that developed CMS-121, and the Salk Institute holds the patent (Currais et al., 2019).

Origin as a fisetin derivative

Fisetin was active in animal models of brain disorders but needed high concentrations in cell assays and had poor bioavailability. The Salk group screened derivatives against iodoacetic acid toxicity in HT22 cells, an in vitro ischemia model, then for glutathione maintenance, anti-inflammatory activity in N9 microglia and PC12 neurite outgrowth. Compound 121 kept all of these activities, and the catechol ring was essential in the quinoline series (Chiruta et al., 2012). A later paper says CMS-121 was selected from 160 synthetic fisetin derivatives (Ates et al., 2024). Models: nerve, microglial and PC12 cell lines.

Reported targets: ACC1, FASN and oxytosis/ferroptosis

Oxytosis is glutamate-triggered nerve cell death driven by glutathione depletion, lipoxygenase activation and reactive oxygen species; ferroptosis, named in 2012, shares its features (Maher et al., 2020). In HT22 cells and rat primary neurons, 1 µM CMS-121 raised ACC1 phosphorylation at serine 79, an inhibitory site set by AMPK; without AMPK, its protection against oxytosis fell. Blocking ACC1 with TOFA or siRNA protected HT22 cells from glutamate, and CMS-121 or ACC1 knockdown protected them from RSL3-induced ferroptosis (Currais et al., 2019).

A drug affinity screen in HT22 and HeLa cells then flagged FASN, and CMS-121 lowered FASN activity in HT22 lysates. CMS-121 or FASN knockdown raised HT22 survival after glutamate, erastin or RSL3 and lowered the lipid peroxidation marker 4-hydroxynonenal (4HNE). With FASN knocked down, CMS-121 still added protection against glutamate and erastin, but not RSL3 (Ates et al., 2020).

Independent laboratories use it as an ACC1 inhibitor in human endothelial cells (Chen et al., 2025) and as a FASN inhibitor in herpes simplex virus 1-infected SH-SY5Y cells (Albano et al., 2025). Models: cell lines and rat primary neurons.

Alzheimer's disease and aging mouse models

Male APPswe/PS1ΔE9 mice, an Alzheimer's disease model, were fed 400 ppm CMS-121 in their diet from 9 to 12 months of age. Spatial memory, disinhibition and contextual fear memory matched wild-type levels, with less hippocampal 4HNE, 15LOX2 and GFAP (Ates et al., 2020).

Female SAMP8 mice fed 200 ppm from 4 to 13 weeks of age had significantly lower hearing thresholds at 12 and 16 kHz and more cochlear ribbon synapses than controls (Pham et al., 2023). Models: transgenic and senescence-accelerated mice.

Metabolic and kidney models

In female SAMP8 mice fed 400 ppm from 9 to 13 months, CMS-121 restored kidney weight, prevented the age-related rise in plasma creatinine and lowered kidney TNFα and NF-κB p65 (Kepchia et al., 2021). In male db/db mice, a leptin receptor-deficient model of type 2 diabetes, 6 months of CMS-121 in food from 5 weeks of age gave better glucose tolerance, lower HbA1c, insulin, triglycerides, free fatty acids and liver inflammation markers, and lower urinary NGAL, clusterin and albumin, markers of kidney damage (Zahid et al., 2023).

In wild-type male C57BL/6 mice on the same schedule, body weight gain was 40 percent lower than in control-fed mice, with better glucose and lipid indexes and more adipose mitochondrial markers; the authors proposed lower de novo lipogenesis as the link (Dafre et al., 2024). Models: SAMP8, db/db and C57BL/6 mice.

Huntington's disease mouse models

R6/2 mice, an aggressive Huntington's disease model, were fed 200 or 400 ppm CMS-121 from about 6 weeks of age. At 13 weeks, forelimb grip strength was significantly higher with 200 ppm, and median survival rose moderately but not significantly at that level only. In slower-progressing YAC128 mice, 200 ppm gave higher forelimb grip strength at 9 months, more open-field movement at 18 months and a 17 percent longer median survival (631 versus 540 days), without changing maximum survival (Ates et al., 2024). Models: R6/2 and YAC128 transgenic mice.

Phase 1 study in healthy adults

The developers' 2024 review describes the toxicology testing behind CMS-121's US Investigational New Drug application (Currais et al., 2024). CMS-121 was generally well tolerated, with mostly mild adverse events.

A metabolite, CMS121-C2, appeared to be the main CMS-121-related species in plasma; elderly subjects had higher exposure and longer half-lives; and food raised exposure by about 50 percent. The report is a preprint (Maher et al., 2025), and PubMed indexes no peer-reviewed version or later trial. Model: human phase 1 study.