DNA pol β Inhibitors

DNA Polymerase β (DNA pol β) is a crucial enzyme in the base excision repair (BER) pathway, playing a vital role in cellular DNA repair processes. Inhibitors of DNA pol β are predominantly chemicals that interfere with DNA synthesis or the enzyme's ability to add nucleotides to a growing DNA strand. The inhibitors of DNA pol β can be categorized based on their mechanism of action. First, there are nucleoside analogs like 2',3'-Dideoxycytidine, Cytarabine, Fludarabine, Gemcitabine, and Clofarabine. These compounds mimic the natural nucleotides but lack a critical hydroxyl group, leading to the termination of DNA chain elongation when incorporated into DNA. They exert their inhibitory effects by being incorporated into the DNA strand during repair synthesis, thereby halting the process mediated by DNA pol β.

Another category includes compounds that indirectly affect DNA pol β by targeting other enzymes involved in DNA synthesis and repair. For example, topoisomerase inhibitors such as Etoposide and Teniposide lead to DNA strand breaks and impede replication, indirectly affecting DNA pol β's activity. Similarly, anthracyclines like Daunorubicin and Mitoxantrone, and intercalating agents such as Actinomycin D, disrupt DNA synthesis and replication, indirectly impeding DNA pol β function. Foscarnet, a unique inhibitor, acts by mimicking pyrophosphate and binding to the enzyme's pyrophosphate binding site, inhibiting the release of pyrophosphate and thus halting DNA chain elongation. Aphidicolin, though less selective, also inhibits DNA pol β by preventing nucleotide incorporation during DNA synthesis.