IWR-1-endo is a potent inhibitor of the Wnt response, blocking a cell-based Wnt/β-catenin pathway reporter response with an IC50 value of 180 nM. IWR-1-endo induces Axin2 protein levels and promotes β-catenin phosphorylation by stabilizing the Axin scaffold destruction complex[1].
IWR-1-endo (10 µM; 1h) attenuated the protective effect of Intermedin/adrenomedullin-2, inhibited cell motility and the number of migrating cells [2]; IWR-1-endo (0.2 µM; 6 days) reduced the protein expression of ALB, AFP, CYP3A4, β-catenin and TCF1 in the nucleus [3]. IWR-1-endo (5-50μM; 24h; 48h) reduced the proliferation of HCT116 cells in a dose- and time-dependent manner [4].
IWR-1-endo (10 μM, ip, q2d; 30 days) partially rescued the cardiomyocyte proliferation defect caused by impaired endocardial Notch signaling[5]. In vivo, IWR-1-endo (5 μM; 24 h) inhibited zebrafish tail fin regeneration with a minimum inhibitory concentration of 0.5 μM. The IWR-1-exo diastereoisomer has much lower activity on the Wnt/β-catenin pathway and has been used as a control[6].
[1]. Lu J, Ma Z, Hsieh JC, Fan CW, Chen B, Longgood JC, Williams NS, Amatruda JF, Lum L, Chen C. Structure-activity relationship studies of small-molecule inhibitors of Wnt response. Bioorg Med Chem Lett. 2009 Jul 15;19(14):3825-7. [2]. [2].Wang Y, Wu Z, Tian J, Mi Y, Ren X, Kang J, Zhang W, Zhou X, Wang G, Li R. Intermedin protects HUVECs from ischemia reperfusion injury via Wnt/β-catenin signaling pathway. Ren Fail. 2019 Nov;41(1):159-166.
[3]. Gao W, Zhou P, Ma X, Tschudy-Seney B, Chen J, Magner NL, Revzin A, Nolta JA, Zern MA, Duan Y. Ethanol negatively regulates hepatic differentiation of hESC by inhibition of the MAPK/ERK signaling pathway in vitro. PLoS One. 2014 Nov 13;9(11):e112698.
[4]. Lee SC, Kim OH, Lee SK, Kim SJ. IWR-1 inhibits epithelial-mesenchymal transition of colorectal cancer cells through suppressing Wnt/β-catenin signaling as well as survivin expression. Oncotarget. 2015 Sep 29;6(29):27146-59.
[5]. Zhao L, Ben-Yair R, Burns CE, Burns CG. Endocardial Notch Signaling Promotes Cardiomyocyte Proliferation in the Regenerating Zebrafish Heart through Wnt Pathway Antagonism. Cell Rep. 2019 Jan 15;26(3):546-554.e5.
[6]. Lu J, Ma Z, Hsieh JC, Fan CW, Chen B, Longgood JC, Williams NS, Amatruda JF, Lum L, Chen C. Structure-activity relationship studies of small-molecule inhibitors of Wnt response. Bioorg Med Chem Lett. 2009 Jul 15;19(14):3825-7.
IWR-1-endo 是一种有效的 Wnt 反应抑制剂，可阻断基于细胞的 Wnt/β-catenin 通路报告基因反应，IC50 值为 180 nM。IWR-1-endo通过稳定 Axin 支架破坏复合物诱导 Axin2 蛋白水平并促进 β-catenin 磷酸化[1]。
IWR-1-endo(10 µM；1h)减弱了Intermedin/adrenomedullin-2的保护作用，抑制了细胞运动能力和迁移细胞的数量[2]；IWR-1-endo(0.2 µM；6天)降低了细胞核内ALB、AFP、CYP3A4、β-catenin和TCF1的蛋白表达[3]。IWR-1-endo(5-50μM；24h；48h)以剂量和时间依赖性方式降低HCT116细胞的增殖[4]。
IWR-1-endo( 10μM , ip, q2d ; 30days )部分挽救了由心内膜Notch信号受损引起的心肌细胞增殖缺陷[5]。在体内试验中，IWR-1-endo （5 μM ; 24h）抑制斑马鱼尾鳍再生，最小抑制浓度为 0.5 μM。IWR-1-exo 非对映异构体对 Wnt/β-catenin 通路的活性要低得多，已被用作对照[6]。