IWP-2 (Synonyms: IWP 2)

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.