Myosin Light Chain Kinase Inhibitor Compounds, Compositions and Related Methods of Use (26088)

A new class of small molecule therapeutic candidates with potential to address areas of disease and injury relevant to tissue barrier dysfunction, such as sepsis, lung injury, microvascular leak, Crohn's disease and related disorders, as well as multi-organ failure.

ADVANTAGES: A small molecule selective inhibitor with drug-like properties suitable for treatment of disease progression and attenuation of tissue injury, with improved survival in critical care situations, where tissue barrier dysfunction, especially microvasculature, is part of disease progression.

SUMMARY: Endothelial or epithelial barrier dysfunction is a key component in diverse disease states such as sepsis and severe burn with their associated organ failure, pulmonary hypertension related tissue injuries, intestinal barrier dysfunctions such as seen in Crohn's disease, and inflammatory lung disorders such as associated with asthma and related respiratory disorders. Effective and safe small molecule therapeutics for these disorders are lacking. Myosin light chain kinase (MLCK) modulates barrier function by regulation of paracellular and intracellular transport processes, and the kinase levels and activity are increased in various animal models of disease and human clinical disease samples. Initial target validation was provided with the development by Northwestern investigators of a selective MLCK210 knockout mouse that is protected from tissue injury, severe edema and death in diverse injury models relevant to sepsis, pulmonary injury, asthma, severe burn, Crohn's disease and inflammatory disorders. Protection from tissue injury and death evidenced by the gene KO is mimicked in wild type mice by bioavailable small molecule and peptide-based selective, kinase activity inhibitors developed by the Northwestern investigators. These diverse target validation studies using genetic KO of the target and small molecule inhibitors of the kinase domain in wild type animals suggest the potential broad utility of MLCK kinase inhibitor drugs.

Leveraging this established platform, the Northwestern investigators have recently developed (this alert) a small molecule, bioavailable, selective MLCK inhibitor lead compound with properties suitable for potential clinical use (Figure 1). This represents a new class of therapeutics with potential to address a major unmet medical need across several areas of disease and injury.

STATUS: Design and synthesis of novel MLCK small molecule inhibitors with drug like properties and in vivo functions has been developed and patent applications filed.

REFERENCE: Biochimica et Biophysica Acta 1763 (2006),1266-1274

Type of Offer: Licensing

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