Among the GWA-identified MMR pathway components, MSH3, an ABC-family ATPase 7 and subunit (together with MSH2) of the heterodimeric MutSβ complex, stands out as an attractive target for small molecule-mediated inhibition. MutSβ recognizes DNA mismatches and insertion loops (>3 bp) and recruits downstream endonucleases (MutLα, β, γ) to effect DNA repair. As a result, the MSH3 subunit provides multiple opportunities for disruption of MutSβ activity, including inhibition of protein-DNA (DNA loop) and proteinprotein (MutL) interactions. Additionally, MSH3 ATPase activity has been linked to the regulation of MutSβ function, suggesting that small molecule-mediated inhibition of this activity could be an effective mechanism for delaying SI of CAG repeats at the HTT locus. Critically, MSH3 lacks the safety liabilities associated with other MMR proteins in this pathway (including MSH2; a shared subunit with the MMR complex MutSα), many of which are linked with hereditary non-polyposis colon cancer (Lynch syndrome). 10 Here, we describe our work to identify small-molecule inhibitors of the MutSβ ATPase function via high-throughput screening (HTS) and report the structures of three small molecule inhibitors bound to MutSβ.