hMLH3 Inhibitors

Chemical inhibitors of hMLH3 can exert their inhibitory effects through various mechanisms which compromise the DNA replication and repair processes where hMLH3 normally functions. Camptothecin and Etoposide target essential enzymes in DNA replication; by inhibiting Topoisomerase I and II, respectively, these compounds create a scenario where the replication fork is destabilized or halted, leading to a decrease in the replication fidelity and an overload of the mismatch repair system, including hMLH3. Trifluridine, a nucleoside analog, incorporates into DNA and disrupts its normal function. This results in the formation of DNA lesions, overwhelming the repair capacity of proteins like hMLH3. Cisplatin and Mitomycin C cause crosslinking of the DNA strands, creating complex DNA damage that requires repair. The crosslinks generated can saturate hMLH3's repair capacity, leading to a functional inhibition of its activity.

Continuing with the indirect inhibition of hMLH3, PARP inhibitors such as Olaparib, Talazoparib, Rucaparib, and Veliparib increase DNA damage by preventing the repair of single-strand breaks, trapping PARP enzymes on DNA, and causing replication forks to stall. This accumulation of DNA damage indirectly inhibits hMLH3 by imposing a high demand on the mismatch repair system that it cannot meet. Methotrexate and 5-Fluorouracil interfere with nucleotide synthesis, which is crucial for DNA replication and repair. By limiting the availability of nucleotides, these drugs indirectly inhibit hMLH3 by reducing the substrates necessary for DNA synthesis, leading to replication stress where hMLH3 is active. Gemcitabine further depletes the pool of deoxynucleotides by inhibiting ribonucleotide reductase, which indirectly inhibits hMLH3 by impairing DNA synthesis and repair, creating an environment where hMLH3 cannot effectively operate. These chemical inhibitors, while not directly targeting hMLH3, lead to a functional inhibition of hMLH3 by compromising the integrity of DNA replication and repair systems, processes that are essential for the proper functioning of hMLH3.