tion in murine macrophages [47]. Both MLS000737267 and MLS000863573 are undesirable from the standpoint of further medicinal chemistry optimization because of the polyphenolic nature. MLS000594187, which bears a resemblance to the above two hits, in that it has a core consisting of three fused 6-membered rings in a phenanthrene-like configuration, belongs to a different chemical class, benzo(c)chromen-6-ones, which has been advanced as selective estrogen receptor b modulators [48]. MLS001196838 was recently characterized as a potent and selective inhibitor of the histone acetyltransferase (HAT) p300, and has been employed to probe HAT’s role in acute myelogenous leukemia [49,50]. A derivative of MLS001076862 has been reported as a modulator of the survival protein MCL-1, and displays cellular activity and thus potential utility for treating hyperproliferative, inflammatory, and other disorders [51]. Of note, MLS001196838 and MLS001076862 contain an exocyclic enone functionality, which may be reactive and would need to be modified prior to an extended optimization of these scaffolds. The pyrimidine-2,4,6- trione central core unit within MLS000587064 derives from barbituric acid, although this compound itself does not belong to the group of typical barbiturates. Most recently, pyrimidine-2,4,6- trione derivatives were shown to be highly effective in a protein aggregation protection assay model of amyotrophic lateral sclerosis and to possess good bioavailability [52]. Lastly, the furanyl- tetrahydromethyl-indole MLS000090966 was recently reported to be an effective inhibitor of tubulin assembly [53]. MLS000587064 and MLS000090966 contain a catechol diether moiety, a recognized chemical liability [54]. Taken together, our analyses have revealed a promising set of structurally diverse heretofore unreported APE1 inhibitors. 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Supporting Information Figure S1 Repeat AP site testing of the three hits whose combination treatments produced large standard deviations (MLS000587064, MLS000090966, and MLS000115025 in Figure 8) upon initial testing. A decrease in the standard deviation was observed for these compounds upon repeat testing, with significant difference (*P,0.05, **P,0.01) between the combina- tion and MMS-alone treatments obtained for MLS000587064 and MLS000115025, confirming the initially-observed enhancement trends. (EPS) Table S1 HTS hits which displayed inhibition in the electro- phoretic separation based assays. (DOCX) Acknowledgments We thank Sam Michael for assistance with the robotic screening and Rajarshi Guha for help with the statistical analyses. Author Contributions Conceived and designed the experiments: DD DK VNV DJM AJ DMW AS. Performed the experiments: DD DK VNV. Analyzed the data: DD DK VNV DJM AJ DMW AS. Contributed reagents/materials/analysis tools: DD DK VNV DJM AJ DMW AS. 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