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
  • 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.

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