Identification of highly selective SIK 1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation

• 成果类型: Article
• 署名作者: Babbe, Holger; Sundberg, Thomas B.; Tichenor, Mark; Seierstad, Mark; Bacani, Genesis; Berstler, James; Chai, Wenying; Chang, Leon; Chung, De Michael; Coe, Kevin; Collins, Bernard; Finley, Michael; Guletsky, Alexander; Lemke, Christopher T.; Mak, Puiying A.; Mathur, Ashok; Mercado-Marin, Eduardo, V; Metkar, Shailesh; Raymond, Donald D.; Rives, Marie -Laure; Rizzolio, Michele; Shaffer, Paul L.; Smith, Russell; Smith, Jacqueline; Steele, Ruth; Steffens, Helena; Suarez, Javier; Tian, Gaochao; Majewski, Nathan; Volak, Laurie P.; Wei, Jianmei; Desai, Prerak T.; Ong, Luvena L.; Koudriakova, Tatiana; Goldberg, Steven D.; Hirst, Gavin; Kaushik, Virendar K.; Ort, Tatiana; Seth, Nilufer; Graham, Daniel B.; Plevy, Scott; Venable, Jennifer D.; Xavier, Ramnik J.; Towne, Jennifer E.
• 署名单位: Johnson & Johnson; Johnson & Johnson USA; Janssen Biotech Inc; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Johnson & Johnson; Johnson & Johnson USA; Janssen Biotech Inc; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13300
• DOI: 10.1073/pnas.2307086120
• 发表日期: 2024-01-02
• 关键词: salt-inducible kinases; phosphorylation; pathogenesis; macrophages; phenotype; gene

摘要

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 phos-phorylation 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.