Proxalutamide (GT0918)

Proxalutamide (GT0918) is a novel orally active androgen receptor (AR) antagonist. Proxalutamide can downregulate the expression of TMPRSS2 and ACE2 to inhibit viral entry into host cells, while also reducing inflammation by activating the Nrf2 pathway^[1-2]. Proxalutamide is applicable for research related to prostate cancer and COVID-19^[3-4].

In vitro, treatment of AR-positive prostate cancer cells (LNCaP, 22RV1) with Proxalutamide (1–10μmol/L) for 48–72 hours. Proxalutamide significantly inhibits cell proliferation and interferes with glutamine metabolism, redox homeostasis, and the de novo pyrimidine synthesis pathway^[5]. Exposure of AR-positive prostate cancer cells (LNCaP, 22RV1) to Proxalutamide (1–40μmol/L) for 24–48 hours. Proxalutamide markedly suppresses cell proliferation and migration, and induces caspase-dependent apoptosis ^[6].

In vivo, pretreatment of mice with Proxalutamide (40mg/kg) once daily for 5 days, followed by induction of inflammatory shock with TNFα (10μg) and IFNγ (20μg). Proxalutamide significantly increased overall survival and alleviated tissue damage caused by cytokine storm, including intestinal villus atrophy, inflammatory cell infiltration, as well as thickening of pulmonary septa and epithelial hyperplasia^[7]. Castrated Balb/C nude mice implanted with LNCaP cells and treated with Proxalutamide (10–40mg/kg) via oral gavage twice daily for 21 days showed significant inhibition of prostate tumor xenograft growth^[8].

References:
[1] Li H, Song G, Zhou Q, et al. Activity of preclinical and phase I clinical trial of a novel androgen receptor antagonist GT0918 in metastatic breast cancer. Breast Cancer Res Treat. 2021 Oct;189(3):725-736.
[2] Yang D, Ju M, Wang H, et al. Efficacy and safety of proxalutamide (GT0918) in severe or critically ill patients with COVID-19: study protocol for a prospective, open-label, single-arm, single-center exploratory trial. BMC Pharmacol Toxicol. 2023 Jun 15;24(1):38.
[3] Şimşek-Yavuz S, Komsuoğlu Çelikyurt FI. An update of anti-viral treatment of COVID-19. Turk J Med Sci. 2021 Dec 17;51(SI-1):3372-3390.
[4] Dellis AE, Papatsoris AG. Perspectives on the current and emerging chemical androgen receptor antagonists for the treatment of prostate cancer. Expert Opin Pharmacother. 2019 Feb;20(2):163-172.
[5] Qu F, Gu Y, Wang Q, et al. Metabolomic profiling to evaluate the efficacy of proxalutamide, a novel androgen receptor antagonist, in prostate cancer cells. Invest New Drugs. 2020 Oct;38(5):1292-1302.
[6] Gu Y, Xue M, Wang Q, et al, Novel Strategy of Proxalutamide for the Treatment of Prostate Cancer through Coordinated Blockade of Lipogenesis and Androgen Receptor Axis. Int J Mol Sci. 2021 Dec 8;22(24):13222.
[7] Qiao Y, Wotring JW, Zheng Y, et al. Proxalutamide reduces SARS-CoV-2 infection and associated inflammatory response. Proc Natl Acad Sci U S A. 2023 Jul 25;120(30):e2221809120.
[8] Zhou T, Xu W, Zhang W, et al. Preclinical profile and phase I clinical trial of a novel androgen receptor antagonist GT0918 in castration-resistant prostate cancer. Eur J Cancer. 2020 Jul;134:29-40.

Proxalutamide (GT0918)是一种新型的、具有口服活性的雄激素受体（AR）拮抗剂，Proxalutamide可下调TMPRSS2和ACE2的表达来抑制病毒进入宿主细胞，同时通过激活Nrf2通路以减少炎症^[1-2]。Proxalutamide可用于前列腺癌和COVID-19的相关研究^[3-4]。

在体外，Proxalutamide（1–10μmol/L）处理AR阳性前列腺癌细胞（LNCaP、22RV1）48–72小时。Proxalutamide显著抑制细胞增殖并干扰谷氨酰胺代谢、氧化还原稳态及嘧啶从头合成通路^[5]。Proxalutamide（1–40μmol/L）处理雄激素受体（AR）阳性前列腺癌细胞（LNCaP、22RV1）24–48小时，Proxalutamide显著抑制细胞增殖与迁移，并诱导caspase依赖性凋亡^[6]。

在体内，Proxalutamide（40mg/kg）预处理小每日一次，持续5天，以TNFα（10μg）和IFNγ（20μg）诱导小鼠炎症性休克，Proxalutamide显著提高了小鼠的总体存活率，并减轻了细胞因子风暴诱导的小肠绒毛萎缩、炎症细胞浸润以及肺间隔增厚和上皮增生等组织损伤^[7]。Proxalutamide（10–40mg/kg）每日两次灌胃处理接种LNCaP细胞的去势Balb/C裸鼠21天，显著抑制前列腺癌移植瘤的生长^[8]。