ZW4864 (free base) is an orally active and selective β-catenin/B-Cell lymphoma 9 protein-protein interaction (β-catenin/BCL9 PPI) inhibitor, with a K_i value of 0.76 μM and an IC_50 value of 0.87 μM [1]. ZW4864 (free base) also demonstrates good pharmacokinetic properties.

ZW4864 (10~40 μM; free base) demonstrates a multifaceted inhibitory effect on β-catenin signaling pathways in various cancer cell lines. Over 24 hours, it diminishes Axin2 and cyclin D1 protein levels in SW480 and MDA-MB-231 cells, and selectively induces apoptosis in triple-negative breast cancer cells (MDA-MB231, MDA-MB-468) with hyperactive β-catenin, sparing normal MCF10A cells, over 72 hours. It also decreases the transcription of β-catenin target genes without affecting HPRT expression, indicating specificity in its action. By binding to β-catenin, ZW4864 disrupts its interaction with BCL9 but not with E-cadherin, thereby selectively targeting β-catenin's oncogenic activity. This compound efficaciously suppresses β-catenin-dependent signaling and invasiveness of cancer cells, as well as TOPFlash luciferase activity in a dose-dependent manner, showing particular potency with IC50 values ranging from 6.3 to 11 μM across different cell lines. Collectively, these findings underscore ZW4864's potential as a targeted therapeutic agent against β-catenin-dependent malignancies.

Administered orally at a dosage of 20 mg/kg, ZW4864 (free base) displays favorable pharmacokinetic properties, achieving an oral bioavailability of 83% in C57BL/6 mice [1]. At a higher dosage of 90 mg/kg, also administered orally, it demonstrates the ability to influence tumor growth in mice [1]. Additionally, ZW4864 (free base) effectively inhibits β-catenin target gene expression in a patient-derived xenograft mouse model, further indicating its potential therapeutic benefits [1].