CMS121 is an orally active acetyl-CoA carboxylase 1 (ACC1) inhibitor [1]. CMS121 exerts potent neuroprotective, anti-inflammatory, antioxidant, and renal protective effects by elevating acetyl-CoA levels and activating AMPK [2-3]. CMS121 is primarily intended for the treatment of Alzheimer's-like neurodegenerative disorders [4].
In SH-SY5Y cells, CMS121 (5μM; 48h) reduces the infectivity of HSV-1 viral particles [5]. In hepatocytes, CMS12 (1μM; 24h) increases ac-STAT3 and p-STAT3 levels [6].
In male db/db mice, long-term CMS121 (9.4mg/kg, 18.8mg/kg; po; 24 weeks) treatment alleviates metabolic imbalance, liver inflammation, and reduces markers of kidney injury [7]. In SAMP8 mice model, treated with CMS121 (17mg/kg; po; 9 weeks) showed significantly reduced auditory brainstem responses threshold drift and increased preservation of inner hair cell ribbon synapses in the mid-frequency range [8].
References:
[1]. Dafre A L, Zahid S, Probst J J, et al. CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction[J]. Aging (Albany NY), 2024, 16(6): 4980.
[2]. Dong J, Li M, Peng R, et al. ACACA reduces lipid accumulation through dual regulation of lipid metabolism and mitochondrial function via AMPK-PPARα-CPT1A axis[J]. Journal of Translational Medicine, 2024, 22(1): 196.
[3]. Currais A, Huang L, Petrascheck M, et al. A chemical biology approach to identifying molecular pathways associated with aging[J]. GeroScience, 2021, 43(1): 353-365.
[4]. Currais A, Raschke W, Maher P. CMS121, a novel drug candidate for the treatment of Alzheimer’s disease and age-related dementia[J]. Journal of Alzheimer’s Disease, 2024, 101(s1): S179-S192.
[5]. Albano C, Trifirò L, Hewelt-Belka W, et al. The impact of fatty acid synthase on HSV-1 infection dynamics[J]. PLoS pathogens, 2025, 21(5): e1013068.
[6]. He Y, Wang S, Liu S, et al. MSL1 promotes liver regeneration by driving phase separation of STAT3 and histone h4 and enhancing their acetylation[J]. Advanced Science, 2023, 10(23): 2301094.
[7]. Zahid S, Dafre A L, Currais A, et al. The geroprotective drug candidate CMS121 alleviates diabetes, liver inflammation, and renal damage in db/db leptin receptor deficient mice[J]. International Journal of Molecular Sciences, 2023, 24(7): 6828.
[8]. Pham T B, Boussaty E C, Currais A, et al. Attenuation of age-related hearing impairment in senescence-accelerated mouse prone 8 (SAMP8) mice treated with fatty acid synthase inhibitor CMS121[J]. Journal of Molecular Neuroscience, 2023, 73(4): 307-315.