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

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

doi:10.1021/acschembio.6b00217

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

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

KU-KIST Graduate School of Converging Science and Technology

Research output: Contribution to journal › Article › peer-review

38 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	2105-2111
Number of pages	7
Journal	ACS Chemical Biology
Volume	11
Issue number	8
DOIs	https://doi.org/10.1021/acschembio.6b00217
Publication status	Published - 2016 Aug 19

ASJC Scopus subject areas

Biochemistry
Molecular Medicine

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10.1021/acschembio.6b00217

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Sundberg, T. B., Liang, Y., Wu, H., Choi, H. G., Kim, N. D., Sim, T., Johannessen, L., Petrone, A., Khor, B., Graham, D. B., Latorre, I. J., Phillips, A. J., Schreiber, S. L., Perez, J., Shamji, A. F., Gray, N. S., & Xavier, R. J. (2016). Development of Chemical Probes for Investigation of Salt-Inducible Kinase Function in Vivo. ACS Chemical Biology, 11(8), 2105-2111. https://doi.org/10.1021/acschembio.6b00217

Sundberg, TB, Liang, Y, Wu, H, Choi, HG, Kim, ND, Sim, T, Johannessen, L, Petrone, A, Khor, B, Graham, DB, Latorre, IJ, Phillips, AJ, Schreiber, SL, Perez, J, Shamji, AF, Gray, NS & Xavier, RJ 2016, 'Development of Chemical Probes for Investigation of Salt-Inducible Kinase Function in Vivo', ACS Chemical Biology, vol. 11, no. 8, pp. 2105-2111. https://doi.org/10.1021/acschembio.6b00217

@article{3e3ccdd9ce2a470482006c8fdcf003b6,

title = "Development of Chemical Probes for Investigation of Salt-Inducible Kinase Function in Vivo",

abstract = "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.",

author = "Sundberg, {Thomas B.} and Yanke Liang and Huixian Wu and Choi, {Hwan Geun} and Kim, {Nam Doo} and Taebo Sim and Liv Johannessen and Adam Petrone and Bernard Khor and Graham, {Daniel B.} and Latorre, {Isabel J.} and Phillips, {Andrew J.} and Schreiber, {Stuart L.} and Jose Perez and Shamji, {Alykhan F.} and Gray, {Nathanael S.} and Xavier, {Ramnik J.}",

note = "Funding Information: Research reported in this publication was supported by funding from the National Institutes of Health Grants K08DK104021 (B.K.), U01DK062432 and P30DK043351 (R.J.X.), and R01AI095499 (N.S.G.); Michael J. Fox Foundation for Parkinson's Research (N.S.G); Claudia Adams Barr Program for Innovative Cancer Research (N.S.G); Crohn's & Colitis Foundation of America Grant 500229 (to R.J.X.); and The Leona M. and Harry B. Helmsley Charitable Trust Grant 500203 (to S.L.S. and R.J.X.). S.L.S. is an Investigator of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

year = "2016",

month = aug,

day = "19",

doi = "10.1021/acschembio.6b00217",

language = "English",

volume = "11",

pages = "2105--2111",

journal = "ACS Chemical Biology",

issn = "1554-8929",

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number = "8",

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T1 - Development of Chemical Probes for Investigation of Salt-Inducible Kinase Function in Vivo

AU - Sundberg, Thomas B.

AU - Liang, Yanke

AU - Wu, Huixian

AU - Choi, Hwan Geun

AU - Kim, Nam Doo

AU - Sim, Taebo

AU - Johannessen, Liv

AU - Petrone, Adam

AU - Khor, Bernard

AU - Graham, Daniel B.

AU - Latorre, Isabel J.

AU - Phillips, Andrew J.

AU - Schreiber, Stuart L.

AU - Perez, Jose

AU - Shamji, Alykhan F.

AU - Gray, Nathanael S.

AU - Xavier, Ramnik J.

N1 - Funding Information: Research reported in this publication was supported by funding from the National Institutes of Health Grants K08DK104021 (B.K.), U01DK062432 and P30DK043351 (R.J.X.), and R01AI095499 (N.S.G.); Michael J. Fox Foundation for Parkinson's Research (N.S.G); Claudia Adams Barr Program for Innovative Cancer Research (N.S.G); Crohn's & Colitis Foundation of America Grant 500229 (to R.J.X.); and The Leona M. and Harry B. Helmsley Charitable Trust Grant 500203 (to S.L.S. and R.J.X.). S.L.S. is an Investigator of the Howard Hughes Medical Institute. Publisher Copyright: © 2016 American Chemical Society.

PY - 2016/8/19

Y1 - 2016/8/19

N2 - 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.

AB - 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.

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U2 - 10.1021/acschembio.6b00217

DO - 10.1021/acschembio.6b00217

M3 - Article

C2 - 27224444

AN - SCOPUS:84983246909

SN - 1554-8929

VL - 11

SP - 2105

EP - 2111

JO - ACS Chemical Biology

JF - ACS Chemical Biology

IS - 8

ER -

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

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