Overexpression of Bcl-2 has been found in a number of nonhematopoietic cancers, including prostate cancer, breast cancer, and colon cancer. Bcl-2 overexpression in these cells has been found to render cells markedly more resistant to the cytotoxic effects of almost all available anti-cancer drugs. Thus, design of Bcl-2 antagonists will promote selective death of cancer cells and present a new approach in cancer therapy. Phase I of this project includes the following objectives: 1) to generate computational model of Bcl-2 and its intracellular ligand, Bax, based on the multi-dimensional NMR structure of a highly homologous protein, Bcl-XL monomer; 2) to utilize the modeled 3-D structure to generate the dynamic trajectories; 3) to generate pharmacophore, templates based on the interaction of Bcl-2/Bax for use in a 3-D computational search for non-peptide small molecule compounds which mimic elements of the protein surface; and 4) to test the biochemical and cellular activities of the selected compounds. The goal of Phase I is to identify antagonist activity in the range of 1-10 muM. The success of Phase I will lead to Phase II activities aimed at refinement of the initial leads into qualified pre-clinical candidates for Bcl- 2 antagonism.
Identification of a small molecule Bcl-2 antagonists has potential applications in the treatment of prostate cancer and other cancer diseases. Prostate cancer is the most common type of cancer among American men and the second-leading cause of cancer death in men. Currently, it is estimated that 179,300 men will be diagnosed with, and 37,000 men will die of prostate cancer each year.
