IWP-2 is a specific inhibitor of Porcupine enzyme in the Wnt signaling pathway, with an IC50 value of 27 nM[1]. IWP-2 is also an ATP-competitive Casein Kinase 1δ (CK1δ) inhibitor, with an IC50 value of 40 nM for CK1δ[2]. In addition, the application of IWP-2 resulted in the inhibition of growth and proliferation of certain cancer cell lines, demonstrating its potential application value in exploring the relationship between Wnt signaling and tumor growth.
In vitro, IWP-2 inhibits the proliferation of A818-6, MiaPaCa2, Panc-1 and other cell lines at low doses, with EC50s of 8.96 µM, 1.90 µM, and 2.33 µM respectively. IWP-2 (2.33 µM) treatment for 48 hours reduced the activity of CK1δ in Panc1 cells[2]. IWP-2 (10-50 µM) treatment significantly inhibited the proliferation, migration, and invasion of MKN28 cells, and enhanced caspase 3/7 activity. IWP-2 treatment inhibits the transcriptional activity of the Wnt/β-catenin signaling pathway and down-regulates the expression levels of Wnt/β-catenin downstream target genes [3].
In vivo, microinjection of IWP-2 into the nucleus accumbens (NAc) dose-dependently blocks amphetamine (AMPH)-induced acquisition and expression of CPP in rats [4]. IWP-2 (60-180 µM, i.t.) dose-dependently inhibits remifentanil-induced activation of the wnt 3a/β-catenin signaling pathway and subsequently reverses the overexpression of c-fos, NR 2 B, and NF-κB [5].
References:
[1] Chen B, et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol. 2009 Feb;5(2):100-7.
[2] GarcÍa-Reyes B, et al. Discovery of Inhibitor of Wnt Production 2 (IWP-2) and Related Compounds As Selective ATP-Competitive Inhibitors of Casein Kinase 1 (CK1) δ/ε. J Med Chem. 2018 May 10;61(9):4087-4102.
[3] Mo M L, Li M R, Chen Z, et al. Inhibition of the Wnt palmitoyltransferase porcupine suppresses cell growth and downregulates the Wnt/β-catenin pathway in gastric cancer[J]. Oncology letters, 2013, 5(5): 1719-1723.
[4] Islam F , Xu K , Beninger R J. Inhibition of Wnt signalling dose-dependently impairs the acquisition and expression of amphetamine-induced conditioned place preference[J].Behavioural brain research, 2017, 326:217-225.
[5] Gao Y , Zhou S , Pan Y ,et al.Wnt3a Inhibitor Attenuates Remifentanil-Induced Hyperalgesia via Downregulating Spinal NMDA Receptor in Rats[J].Journal of Pain Research, 2020, Volume 13:1049-1058.
IWP-2 是Wnt信号通路中Porcupine 酶的特异性抑制剂,IC50值为 27 nM[1]。IWP-2还是一种具有ATP竞争能力的Casein Kinase 1δ(CK1δ) 抑制剂,对CK1δ的IC50值为40 nM[2]。此外,IWP-2的应用导致某些癌细胞系生长和增殖的抑制,显示其在探索Wnt信号与肿瘤生长关系中具有潜在应用价值。
在体外,IWP-2 低剂量抑制A818-6、MiaPaCa2、Panc-1等细胞系的增殖,EC50s 分别为 8.96 µM、1.90 µM、2.33 µM。IWP-2 (2.33 µM)处理48h,降低了Panc1细胞中CK1δ的活性[2]。IWP-2 (10-50 µM)处理显著抑制MKN28细胞的增殖、迁移和侵袭,并增强caspase 3/7活性。IWP-2处理抑制了Wnt/β-catenin信号通路转录活性,下调了Wnt/β-catenin下游靶基因表达水平[3]。
在体内,IWP-2微量注射到伏隔核(NAc)内,将剂量依赖性地阻断大鼠中安非他明诱导的CPP的获得和表达[4]。IWP-2(60-180µM,i.t.)剂量依赖性地抑制瑞芬太尼诱导的wnt 3a/β-catenin信号通路的激活,随后逆转c-fos、NR 2 B和NF-κB的过表达[5]。