2. Academic Validation
  3. Discovery of Novel 3-Phenylpiperidine Derivatives Targeting the β-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

Discovery of Novel 3-Phenylpiperidine Derivatives Targeting the β-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

  • J Med Chem. 2023 Jan 26;66(2):1349-1379. doi: 10.1021/acs.jmedchem.2c01568.
Hao Zhang 1 2,  Chenglong Liu 1,  Qiushi Chen 2 3,  Li-An Shen 1,  Wenting Xiao 1 2,  Jiayi Li 2 3,  Yonghui Wang 1,  Di Zhu 1 4,  Qingwei Zhang 2,  Jianqi Li 2
Affiliations

Affiliations

  • 1 School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
  • 2 Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, 285 Gebai Ni Road, Shanghai 201203, China.
  • 3 School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, China.
  • 4 Department of Pharmacology, School of Basic Medical Science, Fudan University, 138 Yixue Yuan Road, Shanghai 201100, China.
PMID: 36630177 DOI: 10.1021/acs.jmedchem.2c01568
Abstract

Direct disruption of the β-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 β-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 β-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 β-catenin/BCL9 PPI inhibitor and anti-PD-1 Ab in combination.

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