NUCLEAR AND SIGNALLING TARGETS FOR NATURAL PRODUCTS

University Of Virginia Charlottesville, Charlottesville VA

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Abstract

Description: (Applicant's Description) The long-term objective of this Program is the identification of new, effective cancer therapies which act at new targets. To accomplish this objective there will be a concerted research effort to identify and validate targets, develop and implement assays as high throughput screens for natural product extracts and that can be used for bioassay-guided fractionation of such extracts, and carry out secondary assays on leads identified from such screens in vitro and in vivo to assess potential for development to clinical trial. The rapid expansion in knowledge of the genetic and biochemical changes responsible for malignant transformation and molecular evolution of tumor cells provides many new targets for therapeutic intervention. In order to exploit these targets, it will be necessary to use mechanism-based screens at very high throughput to find selective inhibitors of specific targets. It will be important to apply these screens to natural product extracts to exploit the remarkable chemical diversity of secondary metabolites to identify leads. There will be a focus in this Program on areas of cell biology that are felt to be of high potential for generating novel and effective cancer therapeutics. These include: [a] cell cycle regulation particularly focused on kinases involved in regulating the transition from G2 into mitosis, [b] DNA damage response pathways that induce cell cycle arrest at G2 and down-regulate pathways leading to apoptosis, [c] pathways specifically associated with angiogenesis, [d] regulation of chromatin structure, and [e] negative regulatory pathways in hematopoiesis. Specific tasks to be carried out in this Program are: cloning and expression of target proteins, development of assays suitable for screening, proof-of-concept studies to validate targets, running of high throughput screens, bioassays to guide fractionation, secondary evaluation of leads in cellular assays and in vivo, and assistance to the other programs in this NCNPDDG in structure elucidation when necessary. Despite major advances in the therapy of a number of tumors, there is a desparate need for new and more effective therapies for the major solid tumors. It is expected that the novel targets proposed for natural product discovery will yield therapeutic agents which will improve upon responses to current cytotoxic drugs.