AS1842856 is a cell permeable inhibitor that inhibits Foxo1 transcriptional activity with IC50=33 nM.AS1842856 can directly bind activated Foxo1, but does not bind Foxo1 phosphorylated at Ser256. AS1842856 reduces Foxo1 activity only by binding to Foxo1, without affecting its transcription and protein expression. AS1842856 can inhibit autophagy[1-3].
AS1842856(1.0 µM; 0-12 days) continued to inhibit Foxo1, preventing adipocyte differentiation[4]. Treatment of BBC and GBM cancer cells with AS1842856(0.2-1.0 µM)led to increases in FAS (FAS cell surface death receptor) and BIM (BCL2L11) gene expression, as well as increased positivity for markers for apoptosis such as annexin V and propidium iodide[5].
AS1842856-mediated(10 days ;5 mg/kg) chemical inhibition of Foxo1 reduced the expression of the atrophy-related ubiquitin ligases and significantly reversed the adverse cardiac remodeling while improving the contractile functions in the TLR2-KO mice[6].AS1842856(10 mg/kg;i.p.;(P) 7-21(2 weeks)) treatment increases the valve number in Foxc2 heterozygous mice[7].
References:
[1]. Nagashima T, Shigematsu N, et,al. Discovery of novel forkhead box O1 inhibitors for treating type 2 diabetes: improvement of fasting glycemia in diabetic db/db mice. Mol Pharmacol. 2010 Nov;78(5):961-70. doi: 10.1124/mol.110.065714. Epub 2010 Aug 24. PMID: 20736318.
[2]. He J, Zhang A, et,al. The resistant effect of SIRT1 in oxidative stress-induced senescence of rat nucleus pulposus cell is regulated by Akt- Foxo1 pathway. Biosci Rep. 2019 May 10;39(5):BSR20190112. doi: 10.1042/BSR20190112. PMID: 30967498; PMCID: PMC6509061.
[3]. Tanaka H, Nagashima T, et,al. Effects of the novel Foxo1 inhibitor AS1708727 on plasma glucose and triglyceride levels in diabetic db/db mice. Eur J Pharmacol. 2010 Oct 25;645(1-3):185-91. doi: 10.1016/j.ejphar.2010.07.018. Epub 2010 Jul 23. PMID: 20655898.
[4]. Zou P, Liu L, et,al. Targeting Foxo1 with AS1842856 suppresses adipogenesis. Cell Cycle. 2014;13(23):3759-67. doi: 10.4161/15384101.2014.965977. PMID: 25483084; PMCID: PMC4613185.
[5]. Flores D, Lopez A, et,al. The Foxo1 inhibitor AS1842856 triggers apoptosis in glioblastoma multiforme and basal-like breast cancer cells. FEBS Open Bio. 2023 Feb;13(2):352-362. doi: 10.1002/2211-5463.13547. Epub 2023 Jan 16. PMID: 36602390; PMCID: PMC9900086.
[6]. Spurthi KM, Sarikhani M, et,al.Toll-like receptor 2 deficiency hyperactivates the Foxo1 transcription factor and induces aging-associated cardiac dysfunction in mice. J Biol Chem. 2018 Aug 24;293(34):13073-13089. doi: 10.1074/jbc.RA118.001880. Epub 2018 Jun 21. PMID: 29929978; PMCID: PMC6109936.
[7]. Ogunsina O, Banerjee R, et,al.Pharmacological inhibition of Foxo1 promotes lymphatic valve growth in a congenital lymphedema mouse model. Front Cell Dev Biol. 2023 Jan 5;10:1024628. doi: 10.3389/fcell.2022.1024628. PMID: 36742198; PMCID: PMC9890395.
AS1842856是一种细胞渗透性抑制剂,抑制Foxo1转录活性,IC50=33 nM。它可以直接结合活化的Foxo1,但不结合Ser256磷酸化的Foxo1。AS1842856仅通过与Foxo1结合而降低FoxO1活性,而不影响其转录和蛋白表达。AS1842856可以抑制自噬[1-3]。
AS1842856(1.0µM;0 ~ 12days)持续抑制Foxo1,阻止脂肪细胞分化[4]。AS1842856(0.2 ~ 1.0 µM)处理BBC和GBM癌细胞后,FAS (FAS细胞表面死亡受体)和BIM (BCL2L11)基因表达增加,凋亡标志物如膜联蛋白V和碘化丙啶阳性增加[5]。
AS1842856介导(10days;5 mg/kg)的Foxo1化学抑制降低了TLR2-KO小鼠萎缩相关泛素连接酶的表达,改善心脏收缩功能,逆转心脏重构[6]。AS1842856(10 mg/kg;i.p;(P) 7 - 21)处理可增加Foxc2杂合小鼠的瓣膜数[7]。