TDP2 Inhibitors

TDP2 inhibitors are a diverse group of compounds primarily characterized by their indirect mode of action, affecting TDP2's DNA repair capacity. These inhibitors exert their effects not by directly targeting TDP2, but by influencing the cellular DNA damage and repair landscape, thus impacting TDP2 activity. The first group of these inhibitors includes compounds like etoposide, teniposide, doxorubicin, camptothecin, and mitoxantrone. These chemicals primarily function by stabilizing DNA topoisomerase cleavage complexes (etoposide, teniposide, doxorubicin, mitoxantrone) or inhibiting topoisomerase I (camptothecin). This action results in increased DNA damage and strand breaks, subsequently raising the demand for DNA repair mechanisms in which TDP2 is involved. By increasing the substrate load and complexity of DNA damage, these compounds indirectly challenge TDP2's capacity to repair DNA, leading to an inhibition-like effect.

The second group includes DNA-damaging agents like bleomycin, cisplatin, carboplatin, and PARP inhibitors (olaparib, niraparib, rucaparib, veliparib). Bleomycin induces DNA breaks, while cisplatin and carboplatin create DNA crosslinks, all of which contribute to enhanced DNA damage. The PARP inhibitors, on the other hand, interfere with DNA repair processes by inhibiting PARP enzymes, leading to an accumulation of DNA damage. The increased DNA damage from these agents creates a heightened demand for DNA repair activities, indirectly affecting TDP2. TDP2, being a key player in repairing certain types of DNA damage, faces an increased workload due to these agents. This indirect mechanism can lead to a functional inhibition of TDP2 as it struggles to keep pace with the elevated levels of DNA damage.