| abstract |
Cancer is the leading cause of death worldwide. Although cancer is a
common disease, there are no commonly used therapies that can kill cancer cells
without also harming normal cells. Cancer is a disease caused by the uncontrolled
growth of cells due to mutations in their DNA. Tumor suppressor proteins in cells can
prevent transformation: if the tumor suppressor protein is mutated, it cannot prevent
cancer cells from multiplying. P53 is a tumor suppressor protein that is mutated in
50% of all cancers and signaling through pathways involving p53 is inactivated in
almost all human cancers. It has been suggested that restoration of the tumor
suppressor activity of the mutated p53 proteins by small molecules could be a
significant cancer therapy; however, small molecules with desirable efficacy and
safety have yet to be identified.
This project involves the screening and evaluation of small molecules that
were synthesized in the RISE laboratory to find potential anti-tumor agents to target
mutant p53 and restore tumor suppressor activity. One tumor suppressor activity of
p53 is its ability to induce apoptosis in cancer cells. We have developed an assay to
screen a large number of small molecules to evaluate their ability to induce p53-
dependent cell death. This assay measures the growth inhibition activity of small
molecules in two transformed cell lines, one with mutant p53, the colon cancer cell
line DLD1, and the other without p53, H1299, a lung cancer cell line. This is a 96
well plate–based assay and has the capacity for large-scale compound screening.
Using the this assay, we have screened 100 compounds from the RISE library of
compounds and found 20 compounds with increased growth inhibitory activity
against the p53 mutant cells compared to the p53 null cells, indicating p53-dependent
growth inhibition. These potential lead molecules will be tested over a larger range of
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