TAK-448 acetate is an oligopeptide analog that acts as a potent agonist of the KISS1 receptor (GPR54; IC₅₀=460pM, EC₅₀=632pM)[1-2]. TAK-448 acetate is a C‑terminal analog of endogenous kisspeptin‑54. Acute administration stimulates the release of luteinizing hormone (LH) and follicle‑stimulating hormone (FSH), while sustained exposure downregulates the pituitary‑gonadal axis, thereby rapidly reducing testosterone levels. TAK‑448 acetate is primarily utilized in research related to endocrine regulation and prostate cancer therapy [3-4].
In vivo, TAK-448 acetate (in the form of the sustained‑release formulation TAK-448‑SR(1M)) was administered as a single subcutaneous injection (0.03–3mg/kg) to male F344/N Jcl‑rnu/rnu rats bearing VCaP prostate cancer xenografts (starting from week 7 post‑implantation, repeated every 4 weeks). TAK-448 acetate significantly reduced plasma testosterone and LH levels, suppressed the growth of testes, prostate, and seminal vesicles, and rapidly lowered plasma prostate‑specific antigen levels[5]. In a mouse model of metabolic dysfunction‑associated steatotic liver disease (MASLD) using DIAMOND male mice, continuous subcutaneous infusion of TAK‑448 acetate (0.3nmol/h) via osmotic minipumps for 6 weeks, TAK‑448 acetate significantly inhibited hepatic de novo lipogenesis, reduced the synthesis of free fatty acids associated with obesity, diabetes, and hepatocellular carcinoma, ameliorated hepatic steatosis and insulin resistance, and down‑regulated the expression of key lipid‑droplet regulators such as CIDEA and the transcription factor SREBP‑1c[6].
References:
[1] Nishizawa N, Takatsu Y, Kumano S, et al. Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac-d-Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility. J Med Chem. 2016 Oct 13;59(19):8804-8811.
[2] Stalewski J, Hargrove DM, Wolfe M, et al. Additive effect of simultaneous continuous administration of degarelix and TAK-448 on LH suppression in a castrated rat model. Eur J Pharmacol. 2018 Apr 5;824:24-29.
[3] MacLean DB, Matsui H, Suri A, et al. Sustained exposure to the investigational Kisspeptin analog, TAK-448, down-regulates testosterone into the castration range in healthy males and in patients with prostate cancer: results from two phase 1 studies. J Clin Endocrinol Metab. 2014 Aug;99(8):E1445-53.
[4] Matsui H, Tanaka A, Yokoyama K, et al. Chronic administration of the metastin/kisspeptin analog KISS1-305 or the investigational agent TAK-448 suppresses hypothalamic pituitary gonadal function and depletes plasma testosterone in adult male rats. Endocrinology. 2012 Nov;153(11):5297-308.
[5] Ishikawa K, Tanaka A, Kogame A, et al. Usefulness of pharmacokinetic/efficacy analysis of an investigational kisspeptin analog, TAK-448, in quantitatively evaluating anti-tumor growth effect in the rat VCaP androgen-sensitive prostate cancer model. Eur J Pharmacol. 2018 Jun 5;828:126-134.
[6] Izarraras K, Shah A, Prasad K, et al. Kisspeptin Mitigates Hepatic De Novo Lipogenesis in Metabolic Dysfunction-Associated Steatotic Liver Disease. Cells. 2025 Aug 20;14(16):1289.
TAK-448 acetate是一种寡肽类似物，作为有效的KISS1R（GPR54；IC₅₀=460pM，EC₅₀=632pM）激动剂[1-2]。TAK-448 acetate是内源性kisspeptin-54的C末端类似物，通过急性给药可刺激促黄体生成素（LH）和促卵泡生成素（FSH）的释放，而持续暴露则能下调垂体-性腺轴，从而快速降低睾酮水平，TAK-448 acetate主要被运用于内分泌调节及前列腺癌的治疗的相关研究[3-4]。
在体内，TAK-448 acetate（以TAK-448-SR(1M)缓释制剂形式）通过单次皮下注射（0.03–3mg/kg）处理VCaP前列腺癌异种移植模型雄性F344/N Jcl-rnu/rnu大鼠（从接种后第7周开始，每4周给药一次），TAK-448 acetate显著降低血浆睾酮和黄体生成素水平，抑制睾丸、前列腺和精囊重量增长，并快速降低血浆前列腺特异性抗原水平[5]。在代谢功能障碍相关脂肪肝病（MASLD）的DIAMOND雄性小鼠模型中，TAK-448 acetate（0.3nmol/h）通过皮下微渗透泵持续给药6周，TAK-448 acetate显著降低肝脏新生脂肪生成，减少与肥胖、糖尿病和肝细胞癌相关的游离脂肪酸合成，改善肝脏脂肪变性和胰岛素抵抗，并下调脂滴形成关键调节因子CIDEA及转录因子SREBP-1c的表达[6]。