For many years, our laboratories have been interested in discovering hLO selective inhibitors, however, none have had a greater IC50 15-hLO-1/12-hLO ratio than 5., To accelerate our ability to screen for 12-hLO selective inhibitors, we modified the known xylenol orange lipoxygenase assay, , – into an HTP 384-well format and screened the 3104 compounds of the NCI mechanistic, diversity and natural product library (). Sixteen potent 12-hLO inhibitors were found, 10 being relatively selective, which represents a 0.3% proportion of selective 12-hLO inhibitors. By comparison, the HTP screen of the NCI repository found 43 potent inhibitors against 15-hLO-1, with 33 being selective, representing a 1.4% proportion of selective inhibitors. The lower percentage of 12-hLO selective inhibitors versus 15-hLO-1 selective inhibitors is consistent with our previous work with UCSC-MNPs and illustrates the difficulty in targeting 12-hLO. Of the 10 selective 12-hLO inhibitors found by the HTP screen, 4 were organo-mercurials, which were discarded due to potential toxicity. The remaining 6 were subjected to secondary manual screening, with NSC125034 losing all inhibitory activity and NSC661755 (michellamine B) losing its inhibitory selectivity, however, not its potency (IC50 for 12-hLO is 4.9 µM and 7.6 µM for 15-hLO-1). Michellamine B is a natural product, anti-HIV agent, which inhibits protein kinase C (PKC) and has been implicated as a potential anti-cancer treatment. Our discovery that michellamine B inhibits both 12-hLO and 15-hLO-1 but does not inhibit 15-hLO-2, may stimulate further interest in its study as an anti-cancer agent.