Discovery of Tyrosine Kinase 2 Inhibitors for Inflammatory Diseases | SRI International

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Discovery of Tyrosine Kinase 2 Inhibitors

SRI is evaluating novel molecular targets as potential therapeutics for arthritis and sepsis.

Inflammatory diseases encompass a range of serious conditions that affect millions of people in the U.S. alone. For example, rheumatoid arthritis is a chronic, debilitating disease affecting 1.3 million adults in the U.S., while sepsis—a complex syndrome resulting from harmful immune responses to microbial infections or extensive tissue damage—contributes to more than 200,000 deaths annually in the U.S.

Blocking cytokine activity is an established strategy for the treatment of inflammatory diseases, such as rheumatoid arthritis, sepsis, psoriasis, asthma, and inflammatory bowel disease, as well as myeloproliferative disorders. Since some patients do not respond to current anti-cytokine treatments, there is a need to develop new cytokine inhibitors as therapeutic targets.

SRI scientists are evaluating novel molecular targets of several cytokines, with the goal of designing a small-molecule drug to block responses involved in many of these inflammatory diseases. One strategy is to inhibit the signaling pathways initiated by the cytokines. In preliminary studies, SRI researchers have identified small-molecule inhibitors of TYK2, a kinase that relays signals from certain cytokines known to play a role in inflammation. As proof of concept, loss of TYK2 reduces sepsis-induced mortality. Given that TYK2 is selectively required by only a subset of cytokines, TYK2 inhibitors may be less toxic and have fewer side effects.

SRI's future efforts will be directed toward developing compounds with higher selectivity for TYK2 and forging new collaborations to move toward viable treatments for inflammation-based diseases.