XCT790 is a potent and selective inverse agonist for ERRα with an IC50 value of 0.37μM[1]. Estrogen-related receptor α (ERRα) is a ligand-independent, constitutively active orphan nuclear receptor that, through co-activators like PGC-1α, centrally governs energy metabolism, mitochondrial biogenesis, and tumor progression[2]. XCT790 inhibits ERRα-mediated transcriptional activity by disrupting the interaction between ERRα and its co-activator PGC-1α, and is widely used in studies of metabolic diseases and anti-tumor research[3][4].
In vitro, treatment of HepG2 and multidrug-resistant R-HepG2 cells with XCT790 (0–20μM; 48h) concentration-dependently reduced cell viability, decreased mitochondrial mass by 50%, transiently elevated and then collapsed ΔΨm, quadrupled ROS levels, activated caspases 3/7, 8, and 9, reduced ERR and PGC-1 protein levels， and induced apoptosis in 28.7% of the cells[5]. XCT790(10μM; 24–96h) time-dependently decreases the expression of ERRα, inhibits proliferation, promotes apoptosis in both ERα-positive and -negative endometrial cancer cells[6].
In vivo, XCT790 (2.5mg/kg; i.p.; three times per week for 4 weeks) significantly reduced PaTu8988 xenograft tumor volume by 63% and tumor weight by 62%; when combined with gemcitabine (60mg/kg), XCT790 further downregulated the levels of ERRα, Ki67, and Cyclin D1 while upregulating cleaved-caspase-3 level, inducing G0/G1 cell-cycle arrest and apoptosis in BALB/c nude mice[7].
References:
[1] Busch BB, Stevens WC Jr, Martin R, et al. Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha. J Med Chem. 2004;47(23):5593-5596.
[2] Tripathi M, Yen PM, Singh BK. Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases. Int J Mol Sci. 2020;21(5):1645.
[3] De Luca A, Fiorillo M, Peiris-Pagès M, et al. Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells. Oncotarget. 2015;6(17):14777-14795.
[4] Kokabu T, Mori T, Matsushima H, et al. Antitumor effect of XCT790, an ERRα inverse agonist, on ERα-negative endometrial cancer cells. Cell Oncol (Dordr).
[5] Wu F, Wang J, Wang Y, Kwok TT, Kong SK, Wong C. Estrogen-related receptor alpha (ERRalpha) inverse agonist XCT-790 induces cell death in chemotherapeutic resistant cancer cells.
[6] Sun P, Mao X, Gao M, et al. Novel endocrine therapeutic strategy in endometrial carcinoma targeting estrogen-related receptor α by XCT790 and siRNA. Cancer Manag Res. 2018;10:2521-2535.
[7] Liu SL, Liang HB, Yang ZY, et al. Gemcitabine and XCT790, an ERRα inverse agonist, display a synergistic anticancer effect in pancreatic cancer. Int J Med Sci. 2022;19(2):286-298.
XCT790是一种高效、选择性的ERRα反向激动剂，IC50为0.37μM[1]。雌激素相关受体α（ERRα）是一种不依赖配体即可持续活化的孤儿核受体，通过与PGC-1α等共激活因子相互作用，在能量代谢、线粒体生物发生及肿瘤进展中发挥核心调控作用[2]。XCT790通过阻断ERRα与共激活因子PGC-1α的结合抑制ERRα介导的转录活性，被广泛用于代谢性疾病及抗肿瘤研究[3][4]。
体外实验中，XCT790（0–20μM；48h）呈浓度依赖性降低HepG2及多药耐药R-HepG2细胞活力，减少线粒体质量约50%，先短暂升高后迅速降低线粒体膜电位（ΔΨm），使活性氧（ROS）水平升高4倍，激活caspases-3/7、-8和-9，下调ERRα与PGC-1α蛋白水平，并诱导28.7%的细胞凋亡[5]。XCT790（10μM；24–96h）呈时间依赖性下调ERα阳性与阴性子宫内膜癌细胞中ERRα表达，抑制增殖并促进凋亡[6]。
体内实验中，XCT790（2.5mg/kg；腹腔注射；每周3次；持续4周）显著缩小PaTu8988异种移植瘤体积63%、瘤重减少62%；与吉西他滨（60mg/kg）联用时，XCT790进一步下调ERRα、Ki67和Cyclin D1水平，上调cleaved-caspase-3水平，并诱导G0/G1期阻滞和细胞凋亡[7]。