Biochemistry

Inhibiting the Uninhibited

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Science  23 Jul 2010:
Vol. 329, Issue 5990, pp. 370
DOI: 10.1126/science.329.5990.370-b

Combining genetic screens with small-compound libraries is an effective way of finding drug candidates, and identifying the chemical target can offer insight into the mechanisms by which these compounds exert their effects. Aghajan et al. have identified a specific inhibitor for an important and functionally diverse class of enzymes and used it to link amino acid biosynthesis to a disease-relevant signaling pathway. The target of rapamycin (TOR) protein kinase plays an important role in nutrient signaling in eukaryotes and regulates cell growth and proliferation; deregulation of the TOR pathway has been linked to human diseases, including cancer. The authors carried out a screen in yeast to identify small molecules that selectively enhanced the effects of rapamycin, which inhibits TOR. One of the compounds inhibited a member of the Skp1–Cullin–F-box (SCF) ubiquitin ligase family, SCFMet30, which regulates genes involved in methionine biosynthesis and has not previously been linked to the TOR pathway. Thus, this study has identified a potential therapeutic that could be useful in combination with rapamycin in the clinic.

Nat. Biotechnol. 28, 738 (2010).

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