ND-630 (Firsocostat) is an acetyl-CoA carboxylase (ACC) inhibitor that suppresses the activity of ACC1 (IC50=2.1nM) and ACC2 (IC50=6.1nM)[1-2]. ND-630 can inhibit fatty acid synthesis, improve insulin sensitivity, and exert beneficial effects on dyslipidemia[3-4].
In vitro, treatment of prostate cancer cells (PC-3, DU145) with ND-630 (5nM) significantly inhibits cell proliferation, migration, and invasion, while reducing fatty acid and triglyceride synthesis[5]. Pretreatment of mouse primary chondrocytes with ND-630 (5nM), followed by culture under high glucose (20mM) and high insulin (20nM) conditions for 7–10 days, significantly inhibits acetyl-CoA carboxylase (ACC) activity, lowers malonyl-CoA levels, and reduces intracellular lipid accumulation[6].
In vivo, oral administration of ND-630 (5mg/kg; twice daily) to Zucker diabetic fatty (ZDF) rats for 37 days significantly reduces hepatic steatosis, improves insulin sensitivity, decreases weight gain without affecting food intake, and has beneficial effects on dyslipidemia[7]. Oral administration of ND-630 (4–16mg/kg/day) to adenine diet-induced chronic kidney disease (CKD) C57BL/6 mice for 4 weeks significantly lowers serum creatinine and blood urea nitrogen levels, alleviates renal tubular injury and collagen deposition, and mitigates oxidative stress and inflammatory responses[8].
References:
[1] Alkhouri N, Lawitz E, Noureddin M, et al. GS-0976 (Firsocostat): an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 2020 Feb;29(2):135-141.
[2] Kwon Y, Gottmann P, Wang S, et al. Induction of steatosis in primary human hepatocytes recapitulates key pathophysiological aspects of metabolic dysfunction-associated steatotic liver disease. J Hepatol. 2025 Jan;82(1):18-27.
[3] Younis IR, Nelson C, Weber EJ, et al. Pharmacokinetics and Safety of Firsocostat, an Acetyl-Coenzyme A Carboxylase Inhibitor, in Participants with Mild, Moderate, and Severe Hepatic Impairment. J Clin Pharmacol. 2024 Jul;64(7):878-886.
[4] Lawitz EJ, Bhandari BR, Ruane PJ, et al. Fenofibrate Mitigates Hypertriglyceridemia in Nonalcoholic Steatohepatitis Patients Treated With Cilofexor/Firsocostat. Clin Gastroenterol Hepatol. 2023 Jan;21(1):143-152.e3.
[5] Wu YP, Zheng WC, Huang Q, et al. ND630 controls ACACA and lipid reprogramming in prostate cancer by regulating the expression of circKIF18B_003. J Transl Med. 2023 Dec 4;21(1):877.
[6] Liu H, Witzigreuter L, Sathiaseelan R, et al. Obesity promotes lipid accumulation in mouse cartilage-A potential role of acetyl-CoA carboxylase (ACC) mediated chondrocyte de novo lipogenesis. J Orthop Res. 2022 Dec;40(12):2771-2779.
[7] Harriman G, Greenwood J, Bhat S, et al. Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):E1796-805.
[8] Liu X, Peng Y, Wu S, et al. ND-630, an acetyl-CoA carboxylase inhibitor, prevents renal fibrosis in adenine-induced CKD mice. Naunyn Schmiedebergs Arch Pharmacol. 2025 Sep 3.