Identifying Protease Specific Small-Molecule Inhibitors of Ras-converting Enzyme

Mentor: Joe Negri

Ras proteins are frequently mutated in human cancers. Ras-converting enzyme (Rce1p), a protease, catalyzes the cleavage of Ras, thereby activating it. Ras is difficult to drug directly, but preliminary studies have shown the ability to identify inhibitors of Rce1p through high-throughput small molecule screening. Previously, a screen was carried out testing over 300,000 compounds to find inhibitors of Rce1p that may in the future be used as potential cancer treatments.

Whan studied the 714 putative Rce1p inhibitors identified in this screen, to validate the activity of these inhibitors by first confirming the results of the primary screen through a retesting at dose, and then testing the inhibitors against other proteases to make sure they are specific to Rce1p. Whan found that 183 of these compounds passed the retest as Rce1p inhibitors. Of those, 143 did not inhibit another protease called trypsin, and of those, 118 did not inhibit another protease called Ste24. Therefore Whan identified 118 chemical compounds that specifically inhibit the Ras-converting enzyme Rce1p.

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Whan, a senior at Belmont High School, screened through chemical libraries to discover compounds that inhibit the protease activity of Ras-converting enzyme.