Identification of NUDT5 Inhibitors From Approved Drugs

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• NUDT5 plays a crucial role in estrogen signaling pathways implicated in breast cancer development.
• Targeted therapies for NUDT5 are emerging, necessitating efficient drug discovery strategies.
• Drug repositioning offers a time- and cost-effective approach to identify novel therapeutic agents.

Purpose of the Study:

• To identify novel inhibitors of NUDT5 through drug repositioning.
• To evaluate the potential of FDA-approved drugs as NUDT5 inhibitors for breast cancer treatment.

Main Methods:

• Utilized connectivity map-based drug association models to identify candidate drugs.
• Performed molecular docking and molecular dynamic simulations to assess drug-target binding affinity.
• Conducted cell line viability assays to evaluate the efficacy of candidate drugs against MCF7 breast cancer cells.

Main Results:

• Eighteen FDA-approved drugs were identified as potential candidates for NUDT5 inhibition.
• Fourteen drugs demonstrated potential binding to the NUDT5 target based on computational analyses.
• Seven of eight tested drugs suppressed MCF7 breast cancer cell viability.
• Nomifensine and isoconazole exhibited lower IC50 values than established antiestrogens, raloxifene and tamoxifen.

Conclusions:

• Nomifensine and isoconazole are promising candidates for further investigation as NUDT5 inhibitors.
• These drugs warrant extensive pharmacodynamic studies to confirm their therapeutic potential in breast cancer.
• Drug repositioning is a viable strategy for discovering novel targeted therapies for NUDT5-related cancers.