Our Targets are ADP-ribose (ADPr) Hydrolases
There are 6 ADPr Hydrolases in humans that comprise 2 families of enzymes. These proteins are the key regulators of ADPr in every cellular compartment and therefore play critical roles in regulating signaling pathways including disease relevant stress signaling. Each ADPr Hydrolase is function and substrate specific allowing us to target specific disease pathways by targeting them with inhibitors.
ADPr Hydrolases are Novel Targets for
Cancer Stress Pathways
Mis-regulation of ADPr levels has been identified in solid tumors, liquid tumors and cancer models. Inhibiting or knocking down ADPr Hydrolases shows significant promise in animal models and cellular models of cancer.
ADPr Hydrolases and ADPr have shown to regulate multiple cancer relevant cellular stress responses including the following:
- DNA replication stress
- DNA damage repair
- Stress dependent gene expression
- Cytoplasmic stress response
- Immune activation
- ER stress
- Oxidative stress and cytokine expression
ADPr Hydrolase Inhibitors Work in DNA Damage Repair Through a Unique Mechanism
Our studies show that inhibition or knockdown of specific ADPr Hydrolases kills cancers by modulating the therapeutically proven DNA damage and replicative stress responses in new and unique ways.
DNA Repair Enzymes
No Inhibition
- PARP1 self modifies and recruits the binding of DNA repair enzymes
- This binding signals the recruitment of additional repair enzymes to sites of DNA damage and DNA is repaired
PARP1 Inhibition
- Inactive PARP1 becomes trapped on DNA and DNA replication is unable to proceed resulting in replication stress
- Repair enzymes are not recruited to repair DNA damage and PARPi sensitive cancer cells die
ADPr Hydrolase Inhibition
- Repair enzymes are not recruited to repair DNA damage and PARPi sensitive cancer cells die