Grant: Project Grant

All cells in our bodies are programmed to die. This program enables us to get rid of cells that are no longer needed during development, no longer functional or that are diseased. Normally cells that become cancerous trigger this program and die. For a tumor to develop the program has to be shut off. Turning it back on in cancer cells with new drugs called BH3-mimetics has proven to be an effective treatment for several leukemias and is now being tested in other cancers. In contrast, turning off cell death for a short period of time would prevent the neurodegeneration that occurs after a stroke. New BH3-mimetic drugs being developed by pharma companies function by competing with the BH3-proteins that turn on and off programmed cell death. However, we have shown that the drugs have unexpected activities and sometimes do not function because a different region of the BH3-proteins called the membrane binding region (MBR) does more than just bind the proteins to membranes. We are studying these additional functions and have shown for two BH3-proteins (Bim and PUMA) that the MBR binds to the same protein as the BH3-mimetic drugs and thereby prevents the drugs from working. We are now proposing to determine how the MBRs bind to the proteins that BH3-mimetic drugs target and prevents these drugs from working properly. We will also test the idea that new drugs can be developed that prevent the MBRs from binding to drug targets. These drugs will benefit patients with variety of different diseases including cancer, stroke and degenerative diseases. Our proposed experiments are similar to our previous work on BH3-proteins that led to our successful development of inhibitors of Bax, (another programmed cell death regulatory protein). Therefore, we are confident that the results of our proposed research will provide both the rationale and the preclinical data needed to motivate the development of new drugs for cancer and neurodegenerative diseases.