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

Hao Shen; Jiayu Ding; Jiaying Ji; Lingrong Hu; Wenjian Min; Yi Hou; Dawei Wang; Yuanyuan Chen; Liping Wang; Yasheng Zhu; Xiao Wang; Peng Yang

doi:10.1021/acs.jmedchem.4c02574

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. Epub 2025 Jan 10.

Authors

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 K_d 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.

MeSH terms

Animals
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis / drug effects
Breast Neoplasms / drug therapy
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Adhesion Molecules / antagonists & inhibitors
Cell Adhesion Molecules / metabolism
Cell Movement / drug effects
Cell Proliferation* / drug effects
Drug Discovery
Endonucleases
Female
Humans
MCF-7 Cells
Membrane Proteins* / antagonists & inhibitors
Membrane Proteins* / metabolism
Mice
Mice, Inbred BALB C
Mice, Nude
Protein Binding
RNA-Binding Proteins* / antagonists & inhibitors
RNA-Binding Proteins* / metabolism
Small Molecule Libraries* / chemical synthesis
Small Molecule Libraries* / chemistry
Small Molecule Libraries* / pharmacology
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

RNA-Binding Proteins
MTDH protein, human
Membrane Proteins
Antineoplastic Agents
Small Molecule Libraries
SND1 protein, human
Cell Adhesion Molecules
Endonucleases