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.
authors.affiliation: Center for the Development of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Sundberg
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.|Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Yanke
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Huixian
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.|Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.affiliation: Daegu-Gyeongbuk Medical Innovation Foundation , Daegu, 41061, Korea.
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology , Seoul, Korea , 136-791.
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.|Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Liv
authors.initials: L
authors.lastname: Johannessen
authors.affiliation: Center for the Development of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Petrone
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital , Boston, Massachusetts 02114, United States.
authors.forename: Bernard
authors.initials: B
authors.lastname: Khor
authors.affiliation: Program in Medical and Population Genetics, Broad Institute , Cambridge, Massachusetts 02142, United States.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School , Boston, Massachusetts 02114, United States.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Graham
authors.affiliation: Program in Medical and Population Genetics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Isabel J
authors.initials: IJ
authors.lastname: Latorre
authors.affiliation: Center for the Development of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Phillips
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.|Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.|Howard Hughes Medical Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Center for the Development of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Jose
authors.initials: J
authors.lastname: Perez
authors.affiliation: Center for the Science of Therapeutics, Broad Institute , Cambridge, Massachusetts 02142, United States.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.|Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital , Boston, Massachusetts 02114, United States.|Program in Medical and Population Genetics, Broad Institute , Cambridge, Massachusetts 02142, United States.|Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital , Boston, Massachusetts 02114, United States.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020128:Inhibitory Concentration 50; D051379:Mice; D018345:Mice, Knockout; D015335:Molecular Probes / Q000737:chemistry*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015335:Molecular Probes; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases