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ZW4864 Sale

目录号 : GC63560

ZW4864 是一种具有口服活性和选择性的 β catenin/ B-Cell lymphoma 9 蛋白-蛋白相互作用 (β catenin/BCL9 PPI) 抑制剂。ZW4864 抑制 β catenin/BCL9 PPI 的 Ki 值为0.76 μM,IC50 值为 0.87 μM。

ZW4864 Chemical Structure

Cas No.:2632259-93-7

规格 价格 库存 购买数量
5 mg
¥4,500.00
现货
10 mg
¥7,650.00
现货

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产品描述

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 Ki value of 0.76 μM and an IC50 value of 0.87 μM[1].

ZW4864 (10~40 μM; 24 hours; SW480 and MBA-MD-231 cells) decreases the expression levels of Axin2 and cyclin D1 proteins[1].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[1].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[1].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 IC50 of 11 μM. ZW4864 also dose-dependently suppresses the TOPFlash luciferase activities in SW480 and Wnt 3a-activated MDA-MB-468 cells with the IC50s of 7.0 and 6.3 μM, respectively. ZW4864 selectively suppresses transactivation of β-catenin signaling[1].

ZW4864 (20 mg/kg; p.o.) exhibits good pharmacokinetic properties with an oral bioavailability (F) of 83 %[1].ZW4864 (90 mg/kg; p.o.) shows a variation in tumor growth in mice[1].ZW4864 shows good pharmacokinetic properties and effectively suppresses β-catenin target gene expression in the patient-derived xenograft mouse model[1].

[1]. Wang Z, et al. Discovery of an Orally Bioavailable Small-Molecule Inhibitor for the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction. J Med Chem. 2021;64(16):12109-12131.

Chemical Properties

Cas No. 2632259-93-7 SDF
分子式 C33H43ClN6O3 分子量 607.19
溶解度 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 1.6469 mL 8.2347 mL 16.4693 mL
5 mM 0.3294 mL 1.6469 mL 3.2939 mL
10 mM 0.1647 mL 0.8235 mL 1.6469 mL
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Research Update

New ZW4864 Derivatives as Small-Molecule Inhibitors for the β-Catenin/BCL9 Protein-Protein Interaction

ACS Med Chem Lett 2022 Apr 25;13(5):865-870.PMID:PMC9109161DOI:10.1021/acsmedchemlett.2c00068.

A series of 1-(3-(2-amino-2-oxoethoxy)phenyl)piperidine-3-carboxamide derivatives was reported as new small-molecule β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) inhibitors. Compounds 17-21 were discovered to inhibit the β-catenin/BCL9 PPI with K i = 0.85-2.7 μM. The effects of 21 on the β-catenin/BCL9 PPI in cellular context were demonstrated by β-catenin/BCL9 pull-down inhibition and dose-dependent suppression of Wnt/β-catenin signal transactivation. Notably, compound 21 is more potent than ZW4864, a previously reported analogue, in modulating transcription and expression of β-catenin target genes and suppressing survival of β-catenin-dependent cancer cells. The cellular on-target efficacy of 21 was demonstrated by β-catenin rescue experiments. Compound 21 represents a promising starting point for further optimization of β-catenin/BCL9 PPI inhibitors.

Discovery of an Orally Bioavailable Small-Molecule Inhibitor for the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction

J Med Chem 2021 Aug 26;64(16):12109-12131.PMID:34382808DOI:10.1021/acs.jmedchem.1c00742.

Aberrant activation of Wnt/β-catenin signaling is strongly associated with many diseases including cancer invasion and metastasis. Small-molecule targeting of the central signaling node of this pathway, β-catenin, is a biologically rational approach to abolish hyperactivation of β-catenin signaling but has been demonstrated to be a difficult task. Herein, we report a drug-like small molecule, ZW4864, that 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. More importantly, ZW4864 shows good pharmacokinetic properties and effectively suppresses β-catenin target gene expression in the patient-derived xenograft mouse model. This study offers a selective chemical probe to explore β-catenin-related biology and a drug-like small-molecule β-catenin/BCL9 disruptor for future drug development.