Discovery of Novel Raf/Ras Protein Inhibitors

Milton Brown
Anatoly Dritschilo
Usha Kasid

Radiation therapy is used in the treatment of prostate cancer. However, local control of tumors is limited by normal tissue tolerance and a resistant phenotype (30% local failure). Strategies to sensitize prostate cancer cells to radiation offer the potential for improved local control and decreased morbidity. Raf-1, a cytosolic protein serine-threonine kinase, plays an important role in signal transduction pathways of cell proliferation and survival. Activated Raf-1 substitutes for the growth factor requirements of normal or immortalized cells and enhances resistance of tumor cells to the toxic effects of ionizing radiation. Our approach is to develop small molecules that will selectively abrogate the interaction between Raf-1 and Ras and sensitize prostate cancer cells to radiation.