Ann Kimble Hill - Discovery of novel regulators of aldehyde dehydrogenase isoenzymes

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      Publication Details (including relevant citation   information): Parajuli, Bibek, Kimble-Hill, Ann C.,   Khanna, May, Ivanova, Yvelina, Meroueh, Samy, Hurley, Thomas D.,   Chemico-Biological Interactions, 2011,   191 (1–3), pp 153-158

      Abstract: Over the past three years we have been   involved in high-throughput screening in an effort to discover   novel small molecular modulators of aldehyde dehydrogenase (ALDH)   activity. In particular, we have been interested in both the   activation and inhibition of the three commonly studied   isoenzymes, ALDH1A1, ALDH2 and ALDH3A1, as their distinct, yet   overlapping substrate specificities, present a particularly   difficult challenge for inhibitor discovery and design.   Activation of ALDH2 has been shown to benefit cardiovascular   outcome following periods of ischemia and renewed interest in   specific inhibition of ALDH2 has application for alcohol aversion   therapy, and more recently, in cocaine addiction. In contrast,   inhibition of either ALDH1A1 or ALDH3A1 has application in cancer   treatments where the isoenzymes are commonly over-expressed and   serve as markers for cancer stem cells. We are taking two   distinct approaches for these screens: in vitro enzyme activity   screens using chemical libraries and virtual computational   screens using the structures of the target enzymes as filters for   identifying potential inhibitors, followed by in vitro testing of   their ability to inhibit their intended targets. We have   identified selective inhibitors of each of these three isoenzymes   with inhibition constants in the high nanomolar to low micromolar   range from these screening procedures. Together, these inhibitors   provide proof for concept that selective inhibition of these   broad specificity general detoxication enzymes through small   molecule discovery and design is possible.

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