TARGETS最新文献

Vascular endothelial growth factor (VEGF) is a crucial growth factor that mediates tumor angiogenesis, and thus many therapeutic agents are being developed to target VEGF or its receptors in the treatment of cancer. Early-phase clinical data indicate that such agents are effective and might lack the nonspecific toxicities of conventional chemotherapies. The anti-VEGF antibody bevacizumab has also shown promising efficacy in Phase III studies. Further research is required, especially into patient selection, the autocrine and paracrine VEGF effector functions in different malignancies, and the long-term safety of these compounds, but it is probable that VEGF and its receptors will soon be important targets in the treatment of cancer.

Complex diseases such as obesity affect millions of people worldwide and yet the therapeutic options available to tackle their causes are limited. Identifying new drug targets by mapping disease-associated genes is made difficult by the fact that more than one gene might act synergistically to cause the condition. Many existing techniques rely on time-consuming characterisation of multiple genetic markers. A new approach, genome hybrid identity profiling, identifies DNA regions that are ‘identical by descent’ for the entire genomes of two related individuals. Isolating disease-associated genes in this way gives researchers a fast, precise way of identifying potential drug targets for treatment of complex diseases.

G-protein-coupled receptors (GPCRs) are a major opportunity for drug discovery in the post-genomic era. There are thought to be more than 500 therapeutically relevant GPCRs out of a total of over 700 identified to date, although only one, rhodopsin, has been the subject of a full 3D X-ray crystallography study. Two structurally related proteins, bacteriorhodopsin and sensory rhodopsin, which are not GPCRs but are part of the seven-helix membrane receptor family, have also been the subject of X-ray crystallographic studies and have been used in GPCR modeling studies. The significant differences between these rhodopsin structures, the relatively low sequence homology between individual GPCRs, and some difficulties in rationalizing point-mutation data suggests that homology-based molecular modeling alone will not provide the accurate structural information on individual receptors required for ligand design and in silico screening. In the absence of such structural information, several approaches can be used to assist in the discovery of ligands.

Effective categorization and description of targets is as important during lead discovery as it is during target identification and validation. The selection of targets to progress to lead identification, the efficiency of assay development, and the analysis of results from compound testing all benefit from the availability of high-quality target information and appropriate utilization tools during lead discovery. Specifically, associating target information with other information produced during lead generation enables: the assessment of emerging targets with respect to their chemical tractability; the grouping of data from similar targets to aid in the identification of potential lead compounds and ‘privileged structures’; and the results from compound testing to be analysed in the context of their biological target. Maximizing the value of the information remains challenging, and some of the current approaches to target classification might need to be modified or supplemented to be effective in lead discovery.

Ian Humphery-Smith is Professor of Pharmaceutical Proteomics at Utrecht University, The Netherlands, and until recently was a Managing Director and Chief Scientific Officer of Glaucus Proteomics. After a PhD in Parasitology at the University of Queensland, he studied virology and bacteriology in France as a post-doc, before returning to Australia as Course-Coordinator in Medical Microbiology and Immunology at the University of Sydney. During this time, Humphery-Smith took up the posts of Executive Director of Australia's second largest DNA sequencing facility and Director of the Center for Proteomic Research and Gene-Product Mapping, which later became the world's first center to focus on studying the proteome. Humphery-Smith has devoted ten years of research to analyzing proteins in health and disease, and it was his work that originally coined the term ‘proteomics’. He was the first to publish the most complete analysis of an entire proteome in 2000, that of the bacterium Mycoplasma genitalium. He currently serves as a council member of the Human Proteome Organization (HUPO) and has been a prime mover in efforts to have the Human Proteome Project become a formally-ratified international initiative to follow-on from the Human Genome Project.