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Kadariya Y , Tang BQ , Myers CB , Fukui J , Peterson JR , Kruger WD
Chemical Genetic Screening for Compounds That Preferentially Inhibit Growth of Methylthioadenosine Phosphorylase (MTAP)-Deficient Saccharomyces cerevisiae
Journal of Biomolecular Screening. 2011 Jan;16(1) :44-52
PMCID: PMC3019245   
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Methylthioadenosine phosphorylase (MTAP), a key enzyme in the methionine salvage pathway, is inactivated in a variety of human cancers. Since all human tissues express MTAP, it would be of potential interest to identify compounds that selectively inhibit the growth of MTAP-deficient cells. To determine if MTAP inactivation could be targeted, the authors have performed a differential chemical genetic screen in isogenic MTAP(+) and MTAP(-) Saccharomyces cerevisiae. A low molecular weight compound library containing 30,080 unique compounds was screened for those that selectively inhibit growth of MTAP-yeast using a differential growth assay. One compound, containing a 1,3,4-thiadiazine ring, repeatedly showed a differential dose response, with MTAP-cells exhibiting a 4-fold shift in IC50 compared to MTAP(+) cells. Several structurally related derivatives of this compound also showed enhanced growth inhibition in MTAP-yeast. These compounds were also examined for growth inhibition of isogenic MTAP(+) and MTAP-HT1080 fibrosarcoma cells, and 4 of the 5 compounds exhibited evidence of modest but significant increased potency in MTAP-cells. In summary, these studies show the feasibility of differential growth screening technology and have identified a novel class of compounds that can preferentially inhibit growth of MTAP-cells. (Journal of Biomolecular Screening 2011:44-52)
Kadariya, Yuwaraj Tang, Baiqing Myers, Cynthia B. Fukui, Jami Peterson, Jeffrey R. Kruger, Warren D. Sage publications inc Thousand oaks 704ow