The Development of STAT Inhibitors as Novel Anti-Leukemia Agents: Use of Semi-Random Synthesis Technology
In recent years, tremendous advances have been made toward understanding the molecular abnormalities occurring in tumor cells. During this time, however, relatively little progress has been made in the treatment of leukemias and other forms of cancer. The challenge, therefore, is to translate advances in understanding the biology of the cancer cell into a new generation of more effective and less toxic anti-cancer agents. A family of proteins, termed STATs, is key mediators of the growth of normal cells. Recent work in Dr. Frank’s laboratory and others’ has shown that STATs are activated inappropriately in leukemias and many other forms of cancer. In experimental systems, the inhibition of STATs leads to the death of the tumor cells. By contrast, normal cells are relatively insensitive to inhibition of STAT function. Thus, blocking the STAT pathway is an extremely attractive approach for the rational design of anti-cancer agents. Given this background, Dr. Frank proposes to develop molecular inhibitors of STAT function. He will use a novel chemical approach called Semi-Random Synthesis to generate unique molecules likely to function as STAT inhibitors. In this process, molecular building blocks derived from compounds that can inhibit STAT activation are combined under conditions of very high energy. This process will generate unique structures that have a high likelihood of blocking the STAT pathway. In addition, he has developed a system to screen compounds for their ability to inhibit STAT function. These technologies will be combined to isolate compounds that are specific inhibitors of the STAT pathway, and which will be tested for their effects in leukemia and other cancer cells. In this manner, Dr. Frank hopes to identify compounds that might lead to more effective and less toxic treatments for these forms of cancer.