Target Engagement Assays for PARP and DDR Pathway Targets

The DNA Damage Response (DDR) pathway maintains genomic integrity by detecting and repairing DNA damage. DDR involves a complex network of sensors, transducers and effectors that coordinate to identify DNA lesions and initiate appropriate repair processes. This pathway is essential not only in preserving DNA integrity during replication and in response to environmental stressors but also in ensuring proper cell cycle progression and apoptosis. Dysfunctions in DDR components are frequently observed in cancer cells, where they contribute to genomic instability and uncontrolled cell proliferation.

Given its central role in cell cycle progression and cell proliferation, the DDR pathway has become a significant target for anti-cancer therapeutics. Inhibition of the DDR pathway has the potential to sensitize cancer cells to chemotherapy and radiotherapy, which exert cytotoxicity effects by inducing DNA damage. Additionally, due to defects in the DDR pathway, cancer cells are often dependent on the remaining functional pathways for DNA repair. This dependence has been exploited using the principle of synthetic lethality, which enables selective targeting of the cancer cells while minimizing impacts on normal cells. The approval of PARP inhibitors to treat BRCA-mutant cancers is a prominent example of leveraging synthetic lethality in the development of new anti-cancer therapeutics.

NanoBRET® Target Engagement (TE) Assays provide a way to quantitatively measure specific target-compound interactions in live cells. Furthermore, we've adapted NanoBRET® TE Assays to monitor compound binding to target protein in complex with a partner protein, DNA fragments or metabolites, providing additional insights into target engagement by inhibitors against the DDR pathway.