This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Fibrosis is the pathological consequence of the physiological response to tissue injury. Currently, more than 4.5 million patients in the US suffer from diseases that are fibrotic in nature. The chronic nature of these diseases and the severity of the illnesses necessitates a therapeutic suitable for long term therapy. A kinase has been identified as the key signaling molecule in the cytokine pathway responsible for initiation and maintenance of ECM secretion. This kinase also appears to be the most accessible therapeutic target in the pathway. A program is ongoing at Biogen to identify a small molecule inhibitor of this kinase that will be suitable as a therapeutic agent. Structure-based drug design has played an important role in the discovery and optimization of multiple inhibitor series at Biogen. The resolution of these crystals without synchrotron radiation is limiting (typically 4.0-8.0 resolution at home; 2.8-3.5 resolution at BNL. As the program advances towards development, the information gained from our kinase-inhibitor complexes will continue to guide our structure/activity analysis, modeling, and medicinal chemistry efforts as we refine our best series into lead molecules. Additional structures will be invaluable as we continue to probe specific interactions and improve on the specific properties of the molecules (affinity, solubility, pharmacokinetic properties) as we work towards our goal of a small molecule therapeutic for fibrotic disease.
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