The goal of the Molecular Aspects of Drug Design Section is to discover new approaches to the design of drugs against cancer and viral diseases, especially AIDS. The general strategy is to integrate information obtained from biological and molecular studies of disease development with structural data on potential drug targets to design new drugs with greater effectiveness and lower systemic toxicity. Our specific approach is to combine mechanistic, computational, and synthetic chemistry with biochemical/biophysical and biological studies of the candidate drugs. DNA is an attractive target for chemotherapy because of its central role in the life of a cell. The repair of DNA damage is critical to the survival of a cell, whether normal or cancerous. The transcription of DNA into RNA, and the replication of DNA are also essential functions. Thus, in principle, selective targeting of these functions in tumor cells by small molecules may result in novel and highly selective drugs. We have found that the bifunctional agents bisimidazoacridones and the closely related bistriazoloacridones (collectively referred to as BIAs), which were discovered in our laboratory, appear to inhibit the growth human colon cancer cells in tissue culture and in nude mice by blocking the ability of the tumor cells to enter into mitosis. The binding of BIAs to the cellular DNA is recognized as damage that results in a cascade of biochemical events that block the progression of the cell through the cell cycle. If the arrested cells are then treated with inhibitors of cyclin-dependent kinases, which have the effect of forcing the cells to proceed into mitosis, the tumor cells die. The binding of BIAs to DNA involves both intercalation and minor groove binding. We hypothesized that one of the consequences of this mode of binding is the ability of the complex to capture a critical protein involved in repair of DNA damage or in transcription. Consideration of this hypothesis led us to propose that some Bias may be inhibitors of HIV replication. Indeed, several members of the series, especially one molecule now called temacrazine were found to have very potent anti-HIV activity. It was found that the molecular target for temacrazine is a component of transcriptional initiation. Thus, temacrazine and its congeners represent a novel class of potential drugs against HIV. The mode of binding of Bias to DNA led us to design a new class of compounds, represented by the unsymmetrical molecule WMC79, which retain many of the selectivity properties of the original Bias but are now potently cytotoxic to tumor cells. Again, the sensitive cells respond to a DNA damage signal. If the tumor cells contain un-mutated p53 tumor suppressor gene, the tumors die by apoptosis induced by p53-mediated activation of caspase 3. However, some tumors in which p53 is mutated or is not expressed are also highly sensitive to WMC79. These include some leukemia's and pancreatic cancers. These tumors are also killed by apoptosis, but the signaling pathways that lead to cell death are independent of p53. The targeting of drugs to specific receptors on tumor cells is a conceptually attractive method to enhance specificity and to decrease systemic toxicity. We have chosen the gastrin receptor (GR) as a prototype to test this hypothesis. Our work has shown that GR, a member of the G-protein-coupled receptor (GPCR) superfamily, undergoes endocytosis via clathrin-coated pits, is transported to the lysosomes, and recycles to the cell surface. Gastrin, the ligand for GR, is a peptide hormone that can be readily modified, because only the C-terminal tetrapeptide is required for recognition by the receptor. We have attached several cytotoxic moieties to various gastrin-derived peptides. Some of these conjugates have been shown to be very cytotoxic in GR+ cells but relatively benign in GR- cells.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010347-06
Application #
7291738
Study Section
(SBL)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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