2010 - Kenneth H. Pearce
Chemical-Biological Interfaces in Endocrinology: Nuclear Receptors, Modulating Ligands, and Drug Discovery
A basic concept in endocrinology is control of activities and processes at distal sites in the body. Signaling molecules, in some cases non-protein small molecule hormones, traverse the body and ultimately relay their chemically encoded information to a protein receptor at the target tissue. The nuclear receptor (NR) superfamily, particularly the steroid receptor sub-family, contains classic examples of receivers for small chemical messengers. The NR is a well-adapted receptor for this type of function because it not only can specifically bind the small molecule, but it is capable of transducing a complex set of signals, typically transcript-related, encoded by the properties of the ligand. The nature of the information that the ligand bound-NR relays also depends on a complex interplay of factors including coactivator partners and cell type. Our work over the past several years has focused on discovery of novel NR-modulating molecules and understanding the properties of the compound-bound NR through chemistry, crystallography, biophysical, and cellular studies. The ultimate goal of our work is to develop therapeutics of a variety of disease states including metabolic, inflammatory, and cancer-related conditions.