Christine Thomas

Identification of a selective thieno[2,3-c]pyridine inhibitor of COT kinase and TNF-α production

COT (Tpl2 in mice) is a serine/threonine MAP3 kinase that regulates production of TNF-alpha and other pro-inflammatory cytokines such as IL-1beta via the ERK/MAP kinase pathway. As TNF-alpha and IL-1beta are clinically validated targets for therapeutic intervention in rheumatoid arthritis (RA), blocking COT provides a potential avenue for amelioration of disease. Herein we describe identification of a cellular active selective small molecule inhibitor of COT kinase.

Use of parallel-synthesis combinatorial libraries for rapid identification of potent FKBP12 inhibitors

Using simple, inexpensive equipment, we have used solution-phase parallel synthesis to rapidly prepare hundreds of sulfonamide- and urea-containing FKBP inhibitors, resulting in rapid identification of extremely potent compounds in these series.

Immunophilins: The next generation

Publisher Summary This chapter discusses the structural biology of the immunophilins and their ligand complexes; prolyl isomerases, and immunosuppressant drugs; peptidylprolyl isomerase family of proteins; and therapeutic utility of immunophilin ligands in treating neurological disorders. In order to study the biological function and interaction of macromolecules, a detailed structural characterization of the protein and its substrates must be available. Two experimental techniques used to determine three-dimensional structure are X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. Computational modeling is another tool, most commonly used in conjunction with one of the above methods. Because the immunophilins were implicated in the mechanism of action of immunosuppressant drugs early on, and the various immunosuppressant drugs provided excellent selective and high-affinity ligands for FKBP12 and cyclophilin A, three-dimensional structures of the free proteins and their drug complexes were avidly pursued. These structures have provided a wealth of understanding of the structural biology of the two classes of immunophilins, and have provided a structural basis for understanding the increasingly expanding role of these fascinating proteins in cellular processes.