Structure-Guided Optimization of Replication Protein A (RPA)-DNA Interaction Inhibitors

Area of Science:

• Molecular Biology
• Medicinal Chemistry
• Oncology

Background:

• Replication protein A (RPA) is a critical human single-stranded DNA (ssDNA)-binding protein involved in DNA replication, repair, recombination, and DNA-damage response (DDR).
• Targeting RPA-DNA interactions is a promising therapeutic strategy for cancer drug discovery, offering potential for single-agent anticancer activity and synergy with other cancer treatments.

Purpose of the Study:

• To design and synthesize novel RPA inhibitors based on the TDRL-551 scaffold.
• To improve the potency and physicochemical properties of previously identified RPA inhibitors.
• To identify new anticancer agents with enhanced efficacy and drug-like characteristics.

Main Methods:

• Design of new analogues based on the TDRL-551 compound.
• Molecular docking studies to guide structural insights and optimization.
• Structure-activity relationship (SAR) exploration to identify potent compounds.
• Evaluation of RPA inhibitory activity, solubility, and cellular uptake.

Main Results:

• Identification of novel compounds exhibiting low micromolar RPA inhibitory activity.
• The newly synthesized analogues demonstrated improved solubility compared to earlier compounds.
• Compounds showed excellent cellular uptake, indicating good bioavailability.
• Compounds 43, 44, 45, and 46 were identified as particularly promising candidates.

Conclusions:

• The developed novel RPA inhibitors possess significant potential as anticancer agents.
• These compounds offer improved pharmacological properties, making them suitable for further preclinical development.
• The findings support RPA inhibition as a viable strategy for novel cancer therapeutics.