Second, histone acetyltransferases may be inherently difficult to target with small-molecules. Several reported screens versus histone acetyltransferases have turned up few confirmed actives. Third, our triage process may have been overly rigorous at certain stages. Computational filtering may have removed potential actives, though many of the filtered primary actives were PAINS or thiols. It is also possible that assay interference compounds may still inhibit enzymatic activity. However, such compounds may be thiol reactive, a property that is conventionally avoided in lead discovery. Finally, another explanation for the low active rate observed is the HTS MG132 method employed, which may have led to false-negatives. This is difficult to assess in the absence of re-screening our library or employing an alternate screening method. However, two observations downplay this last possibility. First, our method can identify garcinol as well as novel active compounds that were confirmed by two orthogonal assays. Second, we purposefully chose a low activity threshold for IC50 confirmation to minimize the chance of bypassing low potency inhibitors. To summarize, we successfully developed a CPM-based HTS to screen for inhibitors of Rtt109-catalyzed histone acetylation using two full-length physiologically relevant protein complexes. The assay is robust and straightforward, but it is susceptible to many sources of signal artifacts that fortunately can be triaged with appropriate experiments. This assay method can identify garcinol, a reported inhibitor of other KATs, though its mechanism of inhibition is unclear. Since garcinol contains a catechol, it is flagged by PAINS filters. Its activity using our HTS method confirms that active compounds identified by HTS should always be investigated with appropriate orthogonal assays, counterscreens and other follow-up experiments. This HTS identified three confirmed actives following an extensive post-HTS triage. This particular screen, or adaptations thereof, can identify compounds that inhibit Rtt109-catalyzed histone acetylation. These types of inhibitors have potential utility as chemical probes for epigenetic studies as well as minimally toxic antifungals. DNA repair deficiency facilitates accumulation of mutations and accelerates carcinogenesis. These are features of the BEZ235 ataxiatelangiectasia syndrome, seen in patients with loss of function of ataxia telangiectasia mutated protein. On the other hand, robust DNA repair capacity by cancer cells leads to resistance to therapies such as ionizing radiation that are intended to cause lethal DNA damage.