What question did this study set out to answer?

To evaluate the effects of selective SIK2 inhibitors on inflammation and mucosal repair in human models of Ulcerative Colitis.

January 23, 2026

P0156SIK2 selective inhibitors demonstrate dual anti-inflammatory and mucosal repair profiles in human ex vivo models of Ulcerative Colitis

Key Points

To evaluate the effects of selective SIK2 inhibitors on inflammation and mucosal repair in human models of Ulcerative Colitis.
Developed first-in-class selective SIK2 inhibitors using structure-based drug design.
Preincubated whole blood from healthy volunteers with inhibitors and challenged with TLR4 agonist LPS.
Cultured colon explants from Ulcerative Colitis patients with inhibitors and analyzed cytokines and RNA.
Measured cytokines using MSD assays and conducted bulk transcriptomic profiling for gene expression.
Assessed variability in inhibitory effects across different donors.
Selective SIK2 inhibitors significantly reduced LPS-induced proinflammatory cytokines like TNFα and IL-23.
Broad suppression of additional inflammatory mediators relevant to Inflammatory Bowel Disease was observed.
In inflamed explants, SIK2 inhibitors reduced cytokine levels as effectively as upadacitinib.
RNA-seq indicated downregulation of inflammatory pathways and upregulation of mucosal repair genes like mucin-2 and occludin.

Abstract

Abstract Background Salt-inducible kinases (SIKs) amplify proinflammatory gene expression in myeloid cells via phosphorylation of transcriptional coregulators.1 Genetic loss-of-function (LOF) of SIKs in mice or use of pan-SIK inhibitors decreases proinflammatory cytokines (TNFα, IL-12/23, IL-6, and IL-1β) induced by Toll-like receptor (TLR) or IL-1 receptor (IL-1R) agonists. Among the three SIK isoforms, SIK2 exhibits the highest activity in myeloid cells and uniquely enhances the production of anti-inflammatory cytokine IL-10 when selectively inactivated, distinguishing it from SIK1 or SIK3 LOF.2 To date, the lack of highly selective SIK2 inhibitors has prevented the characterization of pharmacological SIK2 inhibition and its therapeutic potential,3,4 particularly in human tissues. Methods Using structure-based drug design, first-in-class SIK2 inhibitors were developed with nanomolar cellular potency and 300-fold selectivity over SIK1 and SIK3. Whole blood from ten healthy volunteers was preincubated with SIK2 selective inhibitors, challenged ex vivo with the TLR4 agonist LPS, and supernatants analyzed by MSD assays and Olink (Target 96 Inflammatory Panel). To assess SIK2 inhibition in diseased tissue, colon explants from Ulcerative Colitis patients were collected and cultured ex vivo with the JAK1 inhibitor upadacitinib or SIK2 selective inhibitors for 18 hours. Cytokines in supernatants were quantified by MSD assays, and biopsy RNA was extracted for bulk transcriptomic profiling. Results In human whole blood, selective SIK2 inhibitors reduced LPS-stimulated proinflammatory cytokines, including TNFα and IL-23. Among ten donors, inter-donor variability was moderate, with nanomolar IC50 values for TNFα and IL-23. Olink profiling revealed broad suppression of additional inflammatory mediators relevant to Inflammatory Bowel Disease, including IL-1β, CCL3, and CXCL10. In inflamed Ulcerative Colitis explants, SIK2 inhibitors matched or surpassed upadacitinib in reducing TNFα and CCL3 secretion. Further, bulk RNA-seq confirmed SIK2 selective inhibitors downregulated inflammatory pathways associated with Inflammatory Bowel Disease, but importantly upregulated expression of genes linked to mucosal repair, including mucin-2 and occludin. Conclusion Our first-in-class, selective SIK2 inhibitors suppress key proinflammatory cytokines while promoting expression of genes related to tissue repair in human ex vivo models of Ulcerative Colitis. These findings support SIK2 as a novel oral therapeutic approach for Inflammatory Bowel Disease, conferring both anti-inflammatory and tissue reparative benefits for patients. References: 1. Lombardi MS, Gilliéron C, Dietrich D, Gabay C. SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces an anti-inflammatory phenotype. J Leukoc Biol. 2016;99(5):711-721. doi:10.1189/jlb.2a0715-307r 2. Darling NJ, Toth R, Arthur JSC, Clark K. Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages. Biochem J. 2017;474(4):521-537. doi:10.1042/BCJ20160646 3. Clark K, MacKenzie KF, Petkevicius K, et al. Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages. Proc Natl Acad Sci U S A. 2012;109(42):16986-16991. doi:10.1073/pnas.1215450109 4. Fu Y, Ma G, Zhang Y, et al. HG-9-91-01 Attenuates Murine Experimental Colitis by Promoting Interleukin-10 Production in Colonic Macrophages through the SIK/CRTC3 Pathway. Inflamm Bowel Dis. 2021;27(11):1821-1831. doi:10.1093/ibd/izab072 Conflict of interest: Mr. Daigle, Scott: Employee of Nimbus Therapeutics Collis, Leon: I am an employee of Nimbus Therapeutics Zhang, Yanbo: I am an employee of Nimbus Therapeutics. Elliott, Ginell: I am an employee of Nimbus Therapeutics Kumar, Sheetal: I am an employee of Nimbus Therapeutics Zhu, Xiaohua: I am an employee of Nimbus Therapeutics Kaila, Neelu: Employee of Nimbus Therapeutics Basavapathruni, Aravind: I am an employee of Nimbus Therapeutics Surapaneni, Sekhar: Employee of Nimbus Therapeutics Scaramozza, Matthew: Employee of Nimbus Therapeutics Kumar, Pavan: Employee of Nimbus Therapeutics Edmondson, Scott: I am an employee of Nimbus Therapeutics Loh, Christine: I am an employee of Nimbus Therapeutics Tummino, Peter: Employee of Nimbus Therapeutics

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