Development of Chemical Probes for Investigation of Salt-Inducible Kinase Function in Vivo

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• 作者：Thomas B. Sundberg ; Yanke Liang ; Huixian Wu ; Hwan Geun Choi ; Nam Doo Kim ; Taebo Sim ; Liv Johannessen ; Adam Petrone ; Bernard Khor ; Daniel B. Graham ; Isabel J. Latorre ; Andrew J. Phillips ; Stuart L. Schreiber ; Jose Perez ; Alykhan F. Shamji ; Nathanael S. Gray ; Ramnik J. Xavier
• 刊名：ACS Chemical Biology
• 出版年：2016
• 出版时间：August 19, 2016
• 年：2016
• 卷：11
• 期：8
• 页码：2105-2111
• 全文大小：420K
• 年卷期：0
• ISSN：1554-8937

文摘

Salt-inducible kinases (SIKs) are promising therapeutic targets for modulating cytokine responses during innate immune activation. The study of SIK inhibition in animal models of disease has been limited by the lack of selective small-molecule probes suitable for modulating SIK function in vivo. We used the pan-SIK inhibitor HG-9-91-01 as a starting point to develop improved analogs, yielding a novel probe 5 (YKL-05-099) that displays increased selectivity for SIKs versus other kinases and enhanced pharmacokinetic properties. Well-tolerated doses of YKL-05-099 achieve free serum concentrations above its IC₅₀ for SIK2 inhibition for >16 h and reduce phosphorylation of a known SIK substrate in vivo. While in vivo active doses of YKL-05-099 recapitulate the effects of SIK inhibition on inflammatory cytokine responses, they did not induce metabolic abnormalities observed in Sik2 knockout mice. These results identify YKL-05-099 as a useful probe to investigate SIK function in vivo and further support the development of SIK inhibitors for treatment of inflammatory disorders.