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Novel RAD51 Inhibitors For Homologous Recombination Suppression And Chemosensitization

Lead Inventor: Philip Connell

SUMMARY

A cell-active RAD51 inhibitor scaffold with an optimized reversible analog that reduces reactivity liabilities and is well suited for research-use commercialization and further oncology lead optimization

The Unmet Need: Selective, biologically stable tools to inhibit RAD51-mediated homologous recombination to study DNA repair biology and overcome resistance to DNA-damaging therapies

  • Homologous recombination is a core pathway used by cells to repair DNA double-strand breaks and replication-associated DNA damage. RAD51 is a central protein in this pathway because it forms nucleoprotein filaments that enable homology search and DNA strand exchange. Elevated RAD51 expression has been reported across multiple tumor types and is associated with enhanced DNA repair capacity and resistance to therapy. This makes RAD51 an attractive target for cancer biology research and, potentially, therapeutic intervention. Earlier RAD51 inhibitor scaffolds demonstrated proof of concept but included reactive chemistry that may limit stability and increase off-target risk in biological systems.

The Proposed Solution: Novel small-molecule RAD51 inhibitors, including a reversible lead analog with improved chemical stability characteristics for use in DNA repair research and further oncology-focused drug development

  • The faculty inventor developed a series of novel small-molecule RAD51 inhibitors, highlighted by an optimized lead compound designed to retain RAD51 inhibitory activity while removing the Michael acceptor reactivity. Importantly, the new compound showed no measurable glutathione reactivity over 24 hours, suggesting improved stability in biological systems. In cell-based assays, the compound specifically inhibited homologous recombination and increased single-strand annealing, consistent with on-target RAD51 pathway disruption. It also sensitized human cells to the cross-linking chemotherapeutic agent mitomycin.

ADVANTAGES

  • Targets a central homologous recombination protein

  • Reversible binding behavior

  • Reduced Michael acceptor reactivity

  • Cellular evidence of HR pathway

APPLICATIONS

  • Development of RAD51-targeted therapeutics

  • DNA repair and genome stability research

  • Synthetic lethality and resistance-mechanism studies

  • Combination studies with DNA-damaging agents