Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation.
- Resource Type
- Article
- Authors
- Babbe, Holger; Sundberg, Thomas B.; Tichenor, Mark; Seierstad, Mark; Bacani, Genesis; Berstler, James; Wenying Chai; Chang, Leon; De Michael Chung; Coe, Kevin; Collins, Bernard; Finley, Michael; Guletsky, Alexander; Lemke, Christopher T.; Puiying A. Mak; Mathur, Ashok; Mercado-Marin, Eduardo V.; Metkar, Shailesh; Raymond, Donald D.; Rives, Marie-Laure
- Source
- Proceedings of the National Academy of Sciences of the United States of America. 1/2/2024, Vol. 121 Issue 1, p1-11. 49p.
- Subject
- *INTERNALLY displaced persons
*MYELOID cells
*CARRIER proteins
*INFLAMMATORY bowel diseases
*INFLAMMATION
*INTESTINES
- Language
- ISSN
- 0027-8424
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. [ABSTRACT FROM AUTHOR]