Validation of the epigenetic reader bromodomain-containing protein 4 (BRD4) as a therapeutic target for treatment of airway remodeling.

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.

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

Structure-based design and optimization were performed to develop small-molecule β-catenin/B-cell lymphoma 9 (BCL9) inhibitors and improve their inhibitory activities. Compound ZL3138 with a novel 1-benzoyl 4-phenoxypiperidine scaffold was discovered to disrupt the β-catenin/BCL9 protein-protein interaction (PPI) with a Ki of 0.96 μM in AlphaScreen competitive inhibition assays and displayed good selectivity for β-catenin/BCL9 over β-catenin/E-cadherin PPIs. The binding mode of new inhibitors was characterized by structure-activity relationship and site-directed mutagenesis studies. Protein pull-down assays indicate that this series of compounds directly binds with β-catenin. Cellular target engagement and co-immunoprecipitation experiments demonstrate that ZL3138 binds with β-catenin and disrupts the β-catenin/BCL9 interaction without affecting the β-catenin/E-cadherin interaction in living cells. Further cell-based studies show that ZL3138 selectively suppresses transactivation of Wnt/β-catenin signaling, regulates transcription and expression of Wnt target genes, and inhibits the growth of Wnt/β-catenin-dependent cancer cells.

Discovery of 1-Benzoyl 4-Phenoxypiperidines as Small-Molecule Inhibitors of the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction.

The canonical Wingless-related integration site signaling pathway plays a critical role in human physiology, and its dysregulation can lead to an array of diseases. β-Catenin is a multifunctional protein within this pathway and an attractive yet challenging therapeutic target, most notably in oncology. This has stimulated the search for potent small-molecule inhibitors binding directly to the β-catenin surface to inhibit its protein–protein interactions and downstream signaling. Here, we provide an account of the claimed (and some putative) small-molecule ligands of β-catenin from the literature. Through in silico analysis, we show that most of these molecules contain promiscuous chemical substructures notorious for interfering with screening assays. Finally, and in line with this analysis, we demonstrate using orthogonal biophysical techniques that none of the examined small molecules bind at the surface of β-catenin. While shedding doubts on their reported mode of action, this study also reaffirms β-catenin as a prominent target in drug discovery.

https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.2c00228

Biophysical Survey of Small-Molecule β-Catenin Inhibitors: A Cautionary Tale

TEADs are transcription factors and core downstream components of the Hippo pathway. Mutations of the Hippo pathway and/or dysregulation of YAP/TAZ culminate in aberrant transcriptional activities of TEADs, which were considered as key contributing factors of mesotheliomas, fibrotic diseases, Alzheimer's diseases, Huntington's diseases, suppressive immune response, and drug resistance, among others. To modulate transcriptional activities of TEADs, several pharmacological approaches have been pursued, including TEAD/YAP protein-protein interaction inhibitors, TEAD PBP inhibitors, and TEAD activators. As summarized in this review, a large number of inhibitors and activators of TEADs have been reported with decent in vitro potencies, a few exerted robust and compelling in vivo efficacies, and three that are undergoing clinical trials for the treatment of human cancers. Despite clinical advancement of the TEAD PBP inhibitors, development of other types TEAD inhibitors and activators generally lags behind. Information showcased herein might benefit discovery of next generation TEAD modulators for treatment of human oncological diseases and beyond. 

A chemical perspective on the modulation of TEAD transcriptional activities: Recent progress, challenges, and opportunities.

Canonical WNT signaling is an important developmental pathway that has attracted increased attention for anticancer drug discovery From the production and secretion of WNT ligands, their binding to membrane receptors, and the β-catenin destruction complex to the expansive β-catenin transcriptional complex, multiple components have been investigated as drug targets to modulate WNT signaling Significant progress in developing WNT inhibitors such as porcupine inhibitors, tankyrase inhibitors, β-catenin/coactivators, protein-protein interaction inhibitors, casein kinase modulators, DVL inhibitors, and dCTPP1 inhibitors has been made, with several candidates (eg, LGK-974, PRI-724, and ETC-159) in human clinical trials Herein we summarize recent progress in the drug discovery and development of small-molecule inhibitors targeting the canonical WNT pathway, focusing on their specific target proteins, in vitro and in vivo activities, physicochemical properties, and therapeutic potential The relevant opportunities and challenges toward maintaining the balance between efficacy and toxicity in effectively targeting this pathway are also highlighted

Small-Molecule Inhibitors Targeting the Canonical WNT Signaling Pathway for the Treatment of Cancer.

Certain embodiments are directed to small molecule selective inhibitors of the BRD4 bromodomain. Compounds described herein can be used to modulate the bronchiolar NFkB-BRD4 axis, which plays a role in acute neutrophilic response to viral molecular patterns. Compounds described herein can be developed as preventive and therapeutic agents for various human diseases and conditions.

Liu Zhiqing

Papers

Small-Molecule Inhibitors Targeting the Canonical WNT Signaling Pathway for the Treatment of Cancer.

Inhibitors of bromodomain-containing protein 4 (brd4)