CMS121は経口活性のアセチル-CoAカルボキシラーゼ1 (ACC1)阻害剤である[1]。CMS121は、アセチル-CoAのレベルを上昇させ、AMPKを活性化することで、有力な神経保護、抗炎症、抗酸化と腎保護作用を発揮する[2-3]。CMS121は、主にアルツハイマー様の神経変性疾患の治療に使われる[4]。
SH-SY5Y細胞で、CMS121 (5μM; 48h)はHSV-1ウイルス粒子の感染性を減らす[5]。肝細胞で、CMS12 (1μM; 24h)はac-STAT3とp-STAT3のレベルを増やす[6]。
雄のdb/dbマウスで、長期的なCMS121 (9.4mg/kg, 18.8mg/kg；経口；24週間)処理は、代謝の不均衡、肝炎症を軽減し、腎損傷のマーカーを減らす[7]。SAMP8マウスモデルで、CMS121 (17mg/kg；経口；9週間)の処理は、聴性脳幹反応閾値ドリフトを著しく減らし、中周波数域で内有毛細胞リボンシナプスの保存性を増やした[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.