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Rad51 Inhibitors for Sensitization to Chemotherapy and Radiation

Published:
Lead Inventor: Philip Connell
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SUMMARY

Optimized small-molecule inhibitors of RAD51 that selectively suppress D-loop formation and homologous recombination

The Unmet Need: Selective agents that suppress homologous recombination repair without off-target toxicity.

  • RAD51 is a central protein in homologous recombination, a DNA repair pathway that helps cells repair double-strand breaks accurately. Many tumors overexpress RAD51 or rely on efficient homologous recombination to survive chemotherapy, radiotherapy, and other DNA-damaging treatments. This makes RAD51 an attractive oncology target, particularly in combination regimens. However, many previously described RAD51 inhibitors act broadly by blocking RAD51 filament formation on single-stranded DNA, which may interfere with multiple RAD51 functions. A more selective approach could improve therapeutic flexibility and create a distinct combination profile.

The Proposed Solution: Optimized small-molecule RAD51 inhibitors that selectively block RAD51 D-loop activity and cellular homologous recombination while preserving RAD51 ssDNA binding and minimizing DNA intercalation liability

  • The faculty inventor developed a new class of optimized small-molecule RAD51 inhibitors that selectively block RAD51-driven D-loop formation and homologous recombination repair in cancer cells while preserving RAD51 binding to ssDNA. Unlike broader RAD51 inhibitors that suppress filament formation altogether, these compounds are designed to interfere specifically with the strand-invasion step most directly linked to DNA double-strand break repair. Through medicinal chemistry optimization and a companion assay to exclude DNA-intercalating false positives, the inventors identified lead analogs with stronger cellular HR inhibition than the original lead, while retaining the desired selective mechanism. The platform is therefore positioned as a differentiated approach to tumor sensitization, especially in combination with chemotherapy, radiation, or other DNA damage response therapies.

FIGURE

(A) Clonogenic survival of three cancer cell lines treated with ionizing radiation followed by outgrowth in the presence of Rad51 inhibitor (red) or control (black). (B)  Rad51-ssDNA binding is necessary for the essential DNA replication activity of Rad51. The inhibitor shows 70% inhibition of D-loop formation at concentrations that inhibit ssDNA binding by less than 50%. The solid lines represent local weighted regression, and the dashed lines represent 95% confidence intervals.

 

ADVANTAGES

ADVANTAGES

  • Mechanistically distinct from broader RAD51 inhibitors
  • Preserves RAD51 binding to ssDNA
  • Improved cellular inhibition of homologous recombination
  • Reduced dsDNA intercalation liability in optimized analogs

 

APPLICATIONS

  • Combination with platinum chemotherapy
  • Radiosensitization
  • Biomarker-selected precision oncology programs
  • Research tools for studying RAD51 biology

 

PUBLICATIONS

 

 

 

 

 

 

 

  • US: 16/081,662