Abstract Background Salt-inducible kinases (SIKs) amplify proinflammatory gene expression in myeloid cells via phosphorylation of transcriptional coregulators.1 Among the three SIK isoforms, SIK2 shows the highest kinase activity in myeloid cells. Genetic loss-of-function (LOF) of SIK2 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.1,2 SIK2 LOF also enhances production of the anti-inflammatory cytokine IL-10, an effect not observed with SIK1 or SIK3 LOF.2 This profile suggests selective SIK2 inhibition may offer therapeutic benefit for inflammatory bowel disease (IBD) and other chronic inflammatory diseases, yet pharmacological SIK2 selective inhibitors have not been previously characterized.3,4 Methods Using structure-based drug design, we developed first-in-class, SIK2-selective small-molecule inhibitors with nanomolar cellular potency, 300-fold selectivity over SIK1 and SIK3, and suitable pharmacokinetic (PK) properties to support in vivo evaluation. We assessed their activity in vitro using human myeloid cells differentiated from peripheral blood and in vivo using anti-CD40 and dextran sodium sulfate (DSS)-induced colitis mouse models. Results In vitro, SIK2-selective inhibitors reduced the production of proinflammatory cytokines in TLR-stimulated primary human macrophages and upregulated the release of anti-inflammatory and tissue repair factors, IL-10 and amphiregulin (AREG). In vivo, SIK2 inhibitors, dosed prophylactically, protected mice from anti-CD40- and DSS-induced colitis. Furthermore, SIK2 inhibitors, dosed therapeutically, accelerated the recovery from DSS-induced colonic damage, exemplified by upregulation of the expression of mucosal barrier integrity and intestinal regeneration markers such as mucin-2 (MUC2), occludin, and zonula occludens-1 (ZO-1) in colon, while inflammatory cytokines and colonic damage markers, including fecal calprotectin and lipocalin-2, were reduced. Moreover, transcriptome analysis of colon tissue samples from SIK2-inhibitor treated mice confirmed the attenuation of intestinal inflammation and upregulation of mucosal healing pathways by selective SIK2 inhibition. Conclusion Our first-in-class highly selective small molecule SIK2 kinase inhibitors represent a unique mechanism of downregulating intestinal inflammation and upregulating mucosal healing, offering a novel oral therapeutic approach for IBD. 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: Dr. Zhang, Yanbo: I am an employee of Nimbus Therapeutics. Collis, Leon: I am an employee of Nimbus Therapeutics Kumar, Sheetal: I am an employee of Nimbus Therapeutics Daigle, Scott: Employee of Nimbus Therapeutics. Zhu, Xiaohua: I am an employee of Nimbus Therapeutics Ackler, Scott: 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 J.: Employee of Nimbus Therapeutics.
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