In summary, we have identified two series of ATPcompetitive MutSβ ATPase inhibitors. Refinement of the hit triage process for the HTS to provide greater rigor in removing artefactual inhibitors revealed a cluster of pteridinecontaining compounds with modest maximal inhibition and potency, as well as a discrete kinase-based lead. Following additional pharmacological study, we demonstrated reversible competitive behavior for these ligands.