Probe Development Summary for Inhibitors of DNA Polymerase Beta
The following assay summarizes ongoing efforts in the development of chemical probes that inhibit human DNA Polymerase Beta. ..more
The following assay summarizes ongoing efforts in the development of chemical probes that inhibit human DNA Polymerase Beta.
The base excision repair system in human cells is a target for therapeutic modulation of the response to irradiation treatment and DNA-damaging drugs. A key enzyme in this system is the bi-functional DNA polymerase known as DNA polymerase Beta (Pol Beta). Although our understanding of the dNMP incorporation reaction by human Pol Beta includes crystal structures representing stages of the catalytic cycle, research with small molecule probes or inhibitors to date has failed to provide the information necessary to effectively target this enzyme. Using an integrated approach involving discovery of small molecule probes for Pol Beta via HTS and medchem optimization in collaboration with the NIH Chemical Genomics Center, validation by crystallography and kinetics along with cell-based validation experiments, we will test the hypothesis that base excision repair can be strategically modulated in human cells by targeting Pol Beta. Thus, we anticipate the Pol Beta-specific probes emerging from this research will serve as starting points in the development of clinical agents for use in downregulation of DNA base excision repair during therapeutic interventions against cancer.
Please see linked BioAssays for all protocols relevant to this probe development project.
Compound ranking comments will be added here as small molecule probes are developed and are annotated with bioassays in PubChem.