Design, synthesis, and biological evaluation of novel 8-substituted quercetin derivatives targeting the ß­catenin/B-cell lymphoma 9 interaction.

The ß-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for aberrantly active Wnt/ß-catenin signaling which actively participates in initiating and progressing of many cancers. Herein, we discovered novel 8-substituted quercetin derivatives with potential inhibitory activities targeting ß-catenin/BCL9 PPI. Among all the derivatives, compound B4 displayed the most promising PPI inhibitory activity with an IC50 value of 2.25 µM in a competitive fluorescence polarization assay and a KD value of 1.44 µM for the ß-catenin protein. Furthermore, B4 selectively inhibited the growth of colorectal cancer (CRC) cells, suppressed the transactivation of Wnt signaling, and downregulated the expression of oncogenic Wnt target gene. Especially, B4 showed potent anti-CRC activity in vivo with the tumor growth inhibition (TGI) of 75.99 % and regulated the tumor immune microenvironment.

RORγt agonist synergizes with CTLA-4 antibody to inhibit tumor growth through inhibition of Treg cells via TGF-ß signaling in cancer.

To date, the overall response rate to checkpoint blockade remains unsatisfactory, partially due to the limited understanding of the tumor immune microenvironment. The retinoic acid-related orphan receptor γt (RORγt) is the key transcription factor of T helper cell 17 (Th17) cells and plays an essential role in tumor immunity. In this study, we used JG-1, a potent and selective small-molecule RORγt agonist to evaluate the therapeutic potential and mechanism of action of targeting RORγt in tumor immunity. JG-1 promotes Th17 cells differentiation and inhibition of regulatory T (Treg) cells differentiation. JG-1 demonstrates robust tumor growth inhibition in multiple syngeneic models and shows a synergic effect with the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) antibody. In tumors, JG-1 not only promotes Th17 cells differentiation and increases C-C Motif Chemokine Receptor 6 (CCR6)- Chemokine (C-C motif) ligand 20 (CCL20) expression, but also inhibits both the expression of transforming growth factor-ß1 (TGF-ß1) and the differentiation and infiltration of Treg cells. In summary, JG-1 is a lead compound showing a potent activity in vitro and robust tumor growth inhibition in vivo with synergetic effects with anti-CTLA-4.

Discovery of Novel 1-Phenylpiperidine Urea-Containing Derivatives Inhibiting ß-Catenin/BCL9 Interaction and Exerting Antitumor Efficacy through the Activation of Antigen Presentation of cDC1 Cells.

Aberrant activation of the Wnt/ß-catenin signaling is associated with tumor development, and blocking ß-catenin/BCL9 is a novel strategy for oncogenic Wnt/ß-catenin signaling. Herein, we presented two novel ß-catenin variations and exposed conformational dynamics in several ß-catenin crystal structures at the BCL9 binding site. Furthermore, we identified a class of novel urea-containing compounds targeting ß-catenin/BCL9 interaction. Notably, the binding modalities of inhibitors were greatly affected by the conformational dynamics of ß-catenin. Among them, 28 had a strong affinity for ß-catenin (Kd = 82 nM), the most potent inhibitor reported. In addition, 13 and 35 not only activate T cells but also promote the antigen presentation of cDC1, showing robust antitumor efficacy in the CT26 model. Collectively, our study demonstrated a series of potent small-molecule inhibitors targeting ß-catenin/BCL9, which can enhance antigen presentation and activate cDC1 cells, delivering a potential strategy for boosting innate and adaptive immunity to overcome immunotherapy resistance.

Discovery of Novel 3-Phenylpiperidine Derivatives Targeting the ß-Catenin/B-Cell Lymphoma 9 Interaction as a Single Agent and in Combination with the Anti-PD-1 Antibody for the Treatment of Colorectal Cancer.

Direct disruption of the ß-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential strategy for colorectal cancer (CRC) treatment through inhibiting oncogenic Wnt activity. Herein, a series of 3-phenylpiperidine derivatives were synthesized and evaluated as ß-catenin/BCL9 PPI inhibitors. Among them, compound 41 showed the best IC50 (0.72 µM) in a competitive fluorescence polarization assay and a KD value of 0.26 µM for the ß-catenin protein. This compound selectively inhibited the growth of CRC cells, suppressed Wnt signaling transactivation, and downregulated oncogenic Wnt target gene expression. In vivo, 41 showed potent anti-CRC activity and promoted the infiltration and function of cytotoxic T lymphocytes while decreasing the infiltration of regulatory T-cells (Tregs). Furthermore, the combination of 41 and the anti-PD-1 antibody (Ab) efficiently enhanced anti-CRC efficacy, first verifying the in vivo efficacy of the small-molecule ß-catenin/BCL9 PPI inhibitor and anti-PD-1 Ab in combination.

Design, synthesis and biological evaluation of quercetin derivatives as novel ß-catenin/B-cell lymphoma 9 protein-protein interaction inhibitors.

The ß-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for the suppression of hyperactive Wnt/ß-catenin signaling that is vigorously involved in cancer initiation and development. Herein, we first described quercetin and its derivatives had potential inhibitory effects on ß-catenin/BCL9 PPI. The most potent compound, quercetin-3'-O-(4-methylpiperazine-1-yl) propyl (C1), directly binded with ß-catenin and disrupted the ß-catenin/BCL9 interaction in both the protein level and the cellular context. C1 also effectively inhibited colorectal cancer in vitro and showed better selectivity in inhibiting hyperactive Wnt/ß-catenin signaling cells like CT26 and HCT116. And we further confirmed that C1 could inhibit CT26 tumor growth in vivo and regulate the tumor immune microenvironment. This study provides a good chemical probe to explore ß-catenin-related biology and a drug-like quercetin derivative as novel ß-catenin/BCL9 PPI inhibitors for further drug development.

Microorganism, Carriers, and Immobilization Methods of the Microbial Self-Healing Cement-Based Composites: A Review.

Low tensile strength, poor elastic modulus, and complex concrete cracking work condition are almost unavoidable due to the intrinsic brittleness. To deal with concrete maintenance and durability, microbial self-healing concretes have been rapidly developed and widely applied recently. The microbial self-healing can specifically patch fractures as well as boost the concrete structure's capacity, durability, and permeability. This paper presents the state-of-the-art in the microbe induced self-healing in cement-based composites. The microorganism and carriers were classified according to the working theory and repair effects. Additionally, the precise efficiency and effect of various technologies are also evaluated for microbial immobilization. Based on the literature review and summary from the perspective of microorganism, carriers, and immobilization methods, challenges and further works are discussed.