John C. Reed, M.D., Ph.D.
Burnham Institute for Medical Research
Abstract:
NF-κB proteins regulate the activity of genes involved in immune system function. These gene regulators become dysfunctional in aggressive Chronic Lymphocytic Leukemias (CLLs), driving leukemic cell growth and protecting leukemic cells against chemotherapy and immunotherapy.
Our proposal seeks to identify, characterize, and optimize chemicals that inhibit NF-κB activity, but which do so in a way that preserves many of the normal functions of NF-κB required for immune defense against bacteria and viruses, while thwarting the adverse effects of NF-κB that contribute to aggressive behaviors of CLL. By performing screens of large collections of chemicals using robotic instrumentation and high-throughput technologies, we have identified candidate chemical inhibitors.
The aims of this project are to: (1) complete the characterization of these pathway-selective NF-κB inhibitors; (2) optimize the potency and selectivity of the compounds using medicinal chemistry; (3) explore the activity of these inhibitors against cultured CLL cells; (4) evaluate the pharmacological properties of the most active compounds and assess dose-limiting toxicities in rodents; and (5) identify a lead compound for testing in mouse models of CLL. Altogether, these studies will lay a foundation for eventual clinical testing.