%0 Journal Article
%T Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation.
%A Babbe H
%A Sundberg TB
%A Tichenor M
%A Seierstad M
%A Bacani G
%A Berstler J
%A Chai W
%A Chang L
%A Chung M
%A Coe K
%A Collins B
%A Finley M
%A Guletsky A
%A Lemke CT
%A Mak PA
%A Mathur A
%A Mercado-Marin EV
%A Metkar S
%A Raymond DD
%A Rives ML
%A Rizzolio M
%A Shaffer PL
%A Smith R
%A Smith J
%A Steele R
%A Steffens H
%A Suarez J
%A Tian G
%A Majewski N
%A Volak LP
%A Wei J
%A Desai PT
%A Ong LL
%A Koudriakova T
%A Goldberg SD
%A Hirst G
%A Kaushik VK
%A Ort T
%A Seth N
%A Graham DB
%A Plevy S
%A Venable JD
%A Xavier RJ
%A Towne JE
%J Proc Natl Acad Sci U S A
%V 121
%N 1
%D 2024 Jan 2
%M 38147543
%F 12.779
%R 10.1073/pnas.2307086120
%X The salt-inducible kinases (SIK) 1-3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. The lack of highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study of the optimal SIK isoform selectivity profile for suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy for developing potent SIK inhibitors that are highly selective against other kinases by engaging two differentiating features of the SIK catalytic site. This effort resulted in SIK1/2-selective probes that inhibit key intracellular proximal signaling events including reducing phosphorylation of the SIK substrate cAMP response element binding protein (CREB) regulated transcription coactivator 3 (CRTC3) as detected with an internally generated phospho-Ser329-CRTC3-specific antibody. These inhibitors also suppress production of pro-inflammatory cytokines while inducing anti-inflammatory interleukin-10 in activated human and murine myeloid cells and in mice following a lipopolysaccharide challenge. Oral dosing of these compounds ameliorates disease in a murine colitis model. These findings define an approach to generate highly selective SIK1/2 inhibitors and establish that targeting these isoforms may be a useful strategy to suppress pathological inflammation.