MMR2 Inhibitors

Chemical inhibitors of MMR2 encompass a range of compounds that impede the protein's ability to conduct its vital role in mismatch repair within the cellular environment. Caffeine, as a phosphodiesterase inhibitor, heightens intracellular cAMP, which in turn activates protein kinase A. The activation of this kinase can lead to the phosphorylation of MMR2, a modification that can alter the protein's activity, effectively reducing its ability to correct mismatches in DNA. Similarly, olaparib, by its action as a PARP inhibitor, leads to the accumulation of single-strand DNA breaks. These breaks can divert the DNA repair machinery toward pathways other than mismatch repair, indirectly taxing MMR2 and hindering its corrective function.

Agents such as etoposide and camptothecin target topoisomerases, stabilizing DNA-topoisomerase complexes and preventing the ligation of DNA strands. This results in an accumulation of DNA breaks, which can overwhelm the cellular repair machinery, including MMR2, and indirectly inhibit its function. Methotrexate, through its inhibition of dihydrofolate reductase, leads to a depletion of nucleotide pools, which can result in an increase in DNA mismatches. These mismatches can exceed the repair capacity of MMR2, leading to an indirect inhibition of its activity. Similarly, cisplatin, by forming DNA adducts and cross-links, can sequester the MMR2 protein and exhaust its repair capabilities, while mitomycin C, through the introduction of cross-links between DNA strands, can overwhelm the DNA repair system, diverting it from its normal mismatch repair function. Additionally, aphidicolin and hydroxyurea, by inhibiting DNA polymerases and ribonucleotide reductase respectively, lead to replication stress and a reduction in the substrates required for DNA repair. This can saturate the MMR2 repair capacity and strain its ability to maintain genomic integrity. Finally, 5-fluorouracil, after being metabolized, leads to an increase in uracil incorporation into DNA, which can overwhelm the repair capacity of MMR2, and actinomycin D, by intercalating into DNA, disrupts replication and transcription, which can lead to a multitude of DNA lesions that the MMR2 protein must process, thereby indirectly inhibiting its function.