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

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

  • J Med Chem. 2024 Jun 24. doi: 10.1021/acs.jmedchem.3c02079.
Wenhua Zhu 1 2,  Cuiting Liu 1 2,  Kang Xi 1 2,  Anqi Li 3,  Li-An Shen 3,  Yana Li 1 2,  Miaomiao Jia 1 2,  Yangbo He 1 2,  Gang Chen 1 2,  Chenglong Liu 3,  Yangqiang Chen 1 2,  Kai Chen 4,  Fan Sun 4,  Daizhou Zhang 5,  Chonggang Duan 5,  Heng Wang 3,  Dongdong Wang 6,  Yujun Zhao 7,  Xiangjing Meng 5,  Di Zhu 3
Affiliations

Affiliations

  • 1 Anhui University of Chinese Medicine, Hefei 230012, China.
  • 2 Yangtze Delta Drug Advanced Research Institute and Yangtze Delta Pharmaceutical College, Nantong 226133, China.
  • 3 School of Basic Medical Sciences, Fudan University, Shanghai 201210, China.
  • 4 Shanghai Jiao Tong University, Shanghai 201210, China.
  • 5 Shandong Academy of Pharmaceutical Science, Jinan 250101, China.
  • 6 DP Technology, Beijing 100080, China.
  • 7 State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai 201203, China.
PMID: 38912577 DOI: 10.1021/acs.jmedchem.3c02079
Abstract

Aberrant activation of the Wnt/β-catenin signaling is associated with tumor development, and blocking β-catenin/BCL9 is a novel strategy for oncogenic Wnt/β-catenin signaling. Herein, we presented two novel β-catenin variations and exposed conformational dynamics in several β-catenin crystal structures at the BCL9 binding site. Furthermore, we identified a class of novel urea-containing compounds targeting β-catenin/BCL9 interaction. Notably, the binding modalities of inhibitors were greatly affected by the conformational dynamics of β-catenin. Among them, 28 had a strong affinity for β-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 β-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.

Figures
Products