Description
ZW4864 is an orally active and selective β catenin/B-Cell lymphoma 9 protein−protein interaction ( β catenin/BCL9 PPI ) inhibitor. ZW4864 inhibits β catenin/BCL9 PPI with a K i value of 0.76 µM and an IC 50 value of 0.87 µMIn VitroZW4864 (10~40 µM; 24 hours; SW480 and MBA-MD-231 cells) decreases the expression levels of Axin2 and cyclin D1 proteins. ZW4864 (10~40 µM; 72 hours; MDA-MB231, MCF10A and MDA-MB-468 cells) selectively triggeres rapid apoptosis of triple-negative breast cancer cells with hyperactive β-catenin signaling while sparing normal mammary epithelial MCF10A cells. ZW4864 (10~40 µM; 24 hours; SW480 and MBA-MD-231 cells) suppresses the transcription of β-catenin target genes in a concentration-dependent manner without affecting the expression of HPRT, a house-keeper gene, in both SW480 and Wnt 3a-activated MDA-MB-231 cells. ZW4864 binds with β-catenin and selectively disrupts the protein−protein interaction (PPI) between B-cell lymphoma 9 (BCL9) and β-catenin while sparing the β-catenin/E-cadherin PPI. ZW4864 dose-dependently suppresses β-catenin signaling activation, downregulates oncogenic β-catenin target genes, and abrogates invasiveness of β-catenin-dependent cancer cells. ZW4864 suppresses TOPFlash luciferase activities in β-catenin expressing HEK293 cells in a dose-dependent manner with an IC 50 of 11 µM. ZW4864 also dose-dependently suppresses the TOPFlash luciferase activities in SW480 and Wnt 3a-activated MDA-MB-468 cells with the IC 50 s of 7.0 and 6.3 µM, respectively. ZW4864 selectively suppresses transactivation of β-catenin signaling. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Western Blot AnalysisCell Line: SW480 and MBA-MD-231 cells Concentration: 10~40 µM Incubation Time: 24 hours Result: Decreased the expression levels of Axin2 and cyclin D1 proteins. Apoptosis AnalysisCell Line: MDA-MB231, MCF10A and MDA-MB-468 cells Concentration: 10~40 µM Incubation Time: 72 hours Result: Selectively triggered rapid apoptosis of triple-negative breast cancer cells with hyperactive β-catenin signaling while sparing normal mammary epithelial MCF10A cells. RT-PCRCell Line: SW480 and MBA-MD-231 cells Concentration: 10~40 µM Incubation Time: 24 hours Result: Suppressed the transcription of β-catenin target genes in a concentration-dependent manner without affecting the expression of HPRT, a house-keeper gene, in both SW480 and Wnt 3a-activated MDA-MB-231 cells.In VivoZW4864 (20 mg/kg; p.o.) exhibits good pharmacokinetic properties with an oral bioavailability (F) of 83 %. ZW4864 (90 mg/kg; p.o.) shows a variation in tumor growth in mice. ZW4864 shows good pharmacokinetic properties and effectively suppresses β-catenin target gene expression in the patient-derived xenograft mouse model. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: C57BL/6 mice Dosage: 20 mg/kg (Pharmacokinetic Analysis) Administration: P.o. Result: Exhibited good pharmacokinetic properties with an oral bioavailability (F) of 83%. Animal Model: Mice Dosage: 90 mg/kg Administration: P.o. Result: Showed a variation in tumor growth in mice.Form:SolidIC50& Target:IC50: 0.87 µM (β catenin/BCL9 PPI),Ki: 0.76 µM(β catenin/BCL9 PPI)