PubMed · 11432275
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M Sharpe. 2001. Smart screening.. https://pubmed.ncbi.nlm.nih.gov/11432275/
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Forward chemical genetics is a new method to systematize the discovery and use of small molecules as tools for basic biological research. This approach requires three basic components: a library of compounds; an assay, in which the library is screened for a cellular or organismal phenotype; and a method to trace an active compound to its biological target. Bioactive compounds have traditionally been isolated from natural product extracts, although 'diversity-oriented synthesis' and commercial compound collections are gaining in prominence. New techniques, such as image-based screening and the cytoblot method, have increased the throughput of phenotypic assays. Strategies are also being developed to streamline target identification using molecular biological approaches.
Schizosaccharomyces pombe is well established as an experimental organism for basic research, with well developed technologies for molecular biology, genetics and cell biology. Its full genome sequence has recently been published. Here, the prerequisites for functional genomics studies in Sch. pombe are examined and compared with those of some established prominent functional genomics model organisms, especially Saccharomyces cerevisiae. It is argued that functional genomics studies in certain areas of cellular and molecular biology could potentially be more efficiently performed in Sch. pombe than in most other experimental organisms.
NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes NAD(+)-dependent oxidation of prostaglandins and other nonprostanoid compounds. This enzyme was found to be dramatically induced in hormone-responsive human prostate cancer cells by androgens [M. Tong, and H. H. Tai, 2000, Biochem. Biophys. Res. Commun. 276, 77-81] and could be involved in prostate tumorigenesis. Inhibitors of this enzyme may be of value in determining the utility of these compounds in cancer chemoprevention. Previously, ciglitazone, an antidiabetic thiazolidinedione, was found to be a potent inhibitor of 15-PGDH. Structure-activity analysis of available thiazolidinediones indicated that the nature of the moiety linking to phenyl ring through ether linkage and benzylidene configuration play important roles in inhibitory potency. Furthermore, N-methylation of 2,4-thiazolidinedione abolished the inhibitory activity. A series of benzylidene thiazolidinediones with varied ring structure and methylene bridge to phenyl ring through ether linkage were synthesized and assayed for inhibitory activity. It was found that compound CT-8 (5-[4-(cyclohexylethoxy)benzylidene]-2,4-thiazolidinedione) was the most potent inhibitor effective at nanomolar range. Kinetic studies revealed that inhibition by this compound was noncompetitive with respect to NAD(+) and uncompetitive with respect to prostaglandin E(2), indicating that the inhibitor interacts with the enzyme at a site distinct from the substrate binding site. This regulatory site appears to overlap with the activator site occupied by imipramine since activation of the enzyme by this activator is competitively inhibited by compound CT-8.