Rad51 Inhibitors for Sensitization to Chemotherapy and Radiation
SUMMARY
- The Rad51 enzyme is over-expressed in many cancers and promotes chemotherapy and radiation resistance by facilitating the homologous recombination necessary for DNA lesion repair. Current therapies that target RAD51 are plagued by significant off-target effects and toxicity.
- Current RAD51 inhibitors block the enzyme’s role in oncogenic homologous recombination, but problematically also inhibit the enzyme from binding and stabilizing single stranded DNA (ssDNA) during replication. The inventors developed a novel class of RAD51 inhibitors that inhibit homologous recombination by blocking D-loop formation, but do not prevent the enzyme from binding ssDNA.
- The invention is a novel class of Rad51 small molecule inhibitors that selectively block the oncogenic DNA lesion repair of the enzyme. These molecules can be used to sensitize tumors to radiation and chemotherapy with limited off-target effects.
- In in vitro assays performed with three different cancer cell lines (U2OS, PC-3, MCF-7), Rad51 inhibitors were shown to sensitize the cell lines to radiation induced DNA damage but did not prevent cellular Rad51 from binding single stranded DNA.
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
- More focused and targeted mechanism of action
- Less off-target effects and toxicity
- Does not block Rad51 binding to ssDNA
- Novel set of compounds
APPLICATIONS
- Cancer small molecules (multiple indications)
- Chemotherapy and radiation combination treatment
PUBLICATIONS
- US: 16/081,662