MSH Inhibitors

Chemical inhibitors of MSH can interfere with its ability to maintain genomic integrity by various means, impacting its interaction with DNA and affecting the protein's structure and stability. Cisplatin, for example, forms crosslinks with DNA that can directly prevent the binding of MSH to DNA or disrupt the subsequent steps in the mismatch repair process. Similarly, methyl methanesulfonate alkylates DNA, which can inhibit MSH's ability to recognize and bind to mismatches. Nitric oxide can modify MSH through nitrosylation, altering the protein's function, particularly its DNA-binding capability. Methoxyacetic acid, through its metabolites, can generate reactive oxygen species that may oxidatively modify MSH, compromising its ability to facilitate the repair of DNA mismatches.

Compounds like cadmium chloride disrupt MSH's function by displacing zinc ions that are essential for the structural integrity of the protein, leading to destabilization. Hydroxyurea, by inhibiting ribonucleotide reductase and thus depleting deoxyribonucleotide pools, indirectly affects MSH by limiting the availability of proper substrates for repair. Agents such as bizelesin and mitomycin C induce DNA crosslinks that can sequester MSH through irreversible binding or by overloading the repair system, resulting in a functional inhibition. Etoposide and doxorubicin, through their interactions with DNA, lead to an increased burden of DNA breaks and intercalation respectively, which can saturate the MSH system and block the access of MSH proteins to DNA mismatches. Lastly, chloroacetaldehyde forms DNA adducts that can either alter MSH directly or obstruct its binding to DNA, thereby inhibiting its function in the DNA mismatch repair pathway.