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Therapeutic disruption of RAD52-ssDNA complexation via novel drug-like inhibitors
Divya S Bhat1, Eva Malacaria2, Ludovica Di Biagi2
1Department of Biochemistry, University of Iowa Carver College of Medicine, 51 Newton Road, Iowa City, IA 52242, USA.
Abstract:
RAD52 protein is a coveted target for anticancer drug discovery. Similar to poly-ADP-ribose polymerase (PARP) inhibitors, pharmacological inhibition of RAD52 is synthetically lethal with defects in genome caretakers BRCA1 and BRCA2 (∼25% of breast and ovarian cancers). Emerging structure activity relationships for RAD52 are complex, making it challenging to transform previously identified disruptors of the RAD52-ssDNA interaction into drug-like leads using traditional medicinal chemistry approaches. Using pharmacophoric informatics on the RAD52 complexation by epigallocatechin (EGC), and the Enamine in silico REAL database, we identified six distinct chemical scaffolds that occupy the same physical space on RAD52 as EGC. All six were RAD52 inhibitors (IC50 ∼23-1200 μM) with two of the compounds (Z56 and Z99) selectively killing BRCA-mutant cells and inhibiting cellular activities of RAD52 at micromolar inhibitor concentrations. While Z56 had no effect on the ssDNA-binding protein RPA and was toxic to BRCA-mutant cells only, Z99 inhibited both proteins and displayed toxicity towards BRCA-complemented cells. Optimization of the Z99 scaffold resulted in a set of more powerful and selective inhibitors (IC50 ∼1.3-8 μM), which were only toxic to BRCA-mutant cells. RAD52 complexation by Z56, Z99 and its more specific derivatives provide a roadmap for next generation of cancer therapeutics.
Insights
New anticancer drugs targeting RAD52 show promise for treating BRCA-mutant cancers. Researchers identified novel RAD52 inhibitors that selectively kill cancer cells with BRCA1/BRCA2 defects, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- RAD52 protein is a key target for anticancer drug discovery, particularly for cancers with BRCA1/BRCA2 mutations.
- Inhibiting RAD52 offers synthetic lethality in BRCA-deficient cancers, similar to PARP inhibitors.
- Developing effective RAD52 inhibitors is challenging due to complex structure-activity relationships.
Purpose of the Study:
- To identify novel chemical scaffolds that inhibit RAD52 function.
- To develop selective RAD52 inhibitors that are toxic to BRCA-mutant cancer cells.
- To provide a foundation for next-generation RAD52-targeted cancer therapeutics.
Main Methods:
- Utilized pharmacophoric informatics and the Enamine REAL database to identify RAD52 inhibitors.
- Screened identified compounds for RAD52 inhibition and cellular activity against BRCA-mutant cells.
- Optimized lead compounds to enhance potency and selectivity.
Main Results:
- Identified six novel chemical scaffolds inhibiting RAD52 (IC50 ∼23-1200 μM).
- Two compounds, Z56 and Z99, selectively killed BRCA-mutant cells.
- Optimized Z99 derivatives demonstrated potent and selective toxicity towards BRCA-mutant cells (IC50 ∼1.3-8 μM).
Conclusions:
- Novel RAD52 inhibitors, particularly optimized Z99 derivatives, show significant potential as targeted cancer therapeutics.
- These compounds offer a promising strategy for treating BRCA-deficient breast and ovarian cancers.
- The identified scaffolds provide a roadmap for developing next-generation RAD52-targeted anticancer drugs.
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