Discovery of Novel Small-Molecule Inhibitors Disrupting the MTDH-SND1 Protein-Protein Interaction

  • J Med Chem. 2025 Jan 23;68(2):1844-1862. doi: 10.1021/acs.jmedchem.4c02574.
Hao Shen  1  2  3 ,  Jiayu Ding  1  2  3 ,  Jiaying Ji  1  2  3 ,  Lingrong Hu  1  2  3 ,  Wenjian Min  1  2  3 ,  Yi Hou  1  2  3 ,  Dawei Wang  1  2  3 ,  Yuanyuan Chen  1  2  3 ,  Liping Wang  1  2  3 ,  Yasheng Zhu  1  2  3 ,  Xiao Wang  1  2  3 ,  Peng Yang  1  2  3
Affiliations
  • 1. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
PMID: 39792778 DOI: 10.1021/acs.jmedchem.4c02574
Abstract

MTDH-SND1 protein-protein interaction (PPI) plays an important role in the initiation and development of tumors, and it is a target for the treatment of breast Cancer. In this study, we identified and synthesized a series of novel small-molecule inhibitors of MTDH-SND1 PPI. The representative compound C19 showed potent activity against MTDH-SND1 PPI with an IC50 of 487 ± 99 nM and tight binding to the SND1-purified protein with a Kd value of 279 ± 17 nM. Compound C19 significantly degraded SND1 and downregulated downstream at the protein level. Further biological evaluations suggested that compound C19 exhibited potent activity against the proliferation of breast Cancer MCF-7 cells with an IC50 value of 626 ± 27 nM, significantly inhibited invasion and migration, and induced cell Apoptosis. In addition, compound C19 exhibited promising tumor growth inhibition in the xenograft model. Our study provides a potential candidate targeting MTDH-SND1 PPI for the treatment of breast Cancer.

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