TARGETS最新文献

The comprehensive molecular approaches of cancer genomics provide unprecedented opportunity for the discovery of potential new targets. Through the establishment of a suite of research programs, focused towards the generation of technological and informational resources for the research community, the National Cancer Institute seeks to nurture the interface of cancer and genomics. The components of the program, including the Cancer Genome Anatomy Project, the Cancer Molecular Analysis Project, and the Initiative in Chemical Genetics, provide a platform for the integration of basic and clinical research, such that the entire research enterprise can work in concert towards improving patient health.

A plethora of important targets for therapeutic intervention occurs in the protein kinase superfamily, one of the most thoroughly investigated groups of drug targets. Kinases have a deep hydrophobic ATP binding site that has been successfully exploited with the discovery of potent ATP-competitive drugs. However, most features of this pocket are well conserved in all protein kinases, which explains why kinase inhibitors typically exhibit a fairly indiscriminate spectrum of activity. Crystal structures of various protein kinases bound to their ligands are described, which begin to explain the observed selectivity profiles of kinase inhibitors. The insights gained from these structures suggest several approaches to improve inhibitor specificity and these approaches are summarized. The exciting potential of new high-throughput methods in structure determination that enable the systematic atomic-resolution investigation of large numbers of inhibitors bound to their various kinase targets will be discussed.

RNA interference (RNAi) has the potential to accelerate greatly the pace of discovery biology. The active RNAi intermediate is the small interfering RNA (siRNA), a discrete nucleic acid duplex that can be generated by several methods and used to directly silence gene expression. The choice of methods employed depends largely on the research or therapeutic objective. In most cases, rational design offers several advantages over random design, including greater predictability of function, higher silencing potency and longer duration of suppression. Of the production methods, chemical synthesis provides the fastest production capability, the highest purity and the easiest scalability for high-throughput strategies. Effective coupling of several methods gives the greatest potential for the application of RNAi across functional genomic and target validation studies. Furthermore, the coupling of RNAi with cellular profiling technologies will provide opportunities to streamline drug discovery significantly.

The publication of the sequence of the human genome revealed that the gene count in humans is much lower than previously estimated. Although textbooks usually place the number at 100,000, it is currently estimated that the human genome contains no more than 30,000 protein-coding genes. How can the great complexity of human life be explained by this number, which is less than twice the number of genes in the primitive worm C. elegans? The answer probably lies in the recent discovery that about half of all human genes undergo alternative splicing. This paper reviews the broad implications of alternative splicing for the drug-discovery process.