Sundberg, Thomas B. Liang, Yanke Wu, Huixian Choi, Hwan Geun Kim, Nam Doo Sim, Taebo Johannessen, Liv Petrone, Adam Khor, Bernard Graham, Daniel B. Latorre, Isabel J. Phillips, Andrew J. Schreiber, Stuart L. Perez, Jose Shamji, Alykhan F. Gray, Nathanael S. Xavier, Ramnik J. 2024-01-20T03:34:17Z 2024-01-20T03:34:17Z 2021-09-05 2016-08 1554-8929 https://pubs.kist.re.kr/handle/201004/123831 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. English AMER CHEMICAL SOC SIK2 MICE PHOSPHORYLATION INFLAMMATION MACROPHAGES HOMEOSTASIS ADIPOCYTES CANCER HDAC4 CELLS Development of Chemical Probes for Investigation of Salt-Inducible Kinase Function in Vivo Article 10.1021/acschembio.6b00217 1 ACS CHEMICAL BIOLOGY, v.11, no.8, pp.2105 - 2111 ACS CHEMICAL BIOLOGY 11 8 2105 2111 scie scopus 000381847700004 2-s2.0-84983246909 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article SIK2 MICE PHOSPHORYLATION INFLAMMATION MACROPHAGES HOMEOSTASIS ADIPOCYTES CANCER HDAC4 CELLS SIK