دورية أكاديمية
Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation.
| العنوان: | Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation. |
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| المؤلفون: | Babbe H; Janssen Research and Development, LLC., Spring House, PA 19477., Sundberg TB; Broad Institute of MIT and Harvard, Center for the Development of Therapeutics, Cambridge, MA 02142., Tichenor M; Janssen Research and Development, LLC., San Diego, CA 92121., Seierstad M; Janssen Research and Development, LLC., San Diego, CA 92121., Bacani G; Janssen Research and Development, LLC., San Diego, CA 92121., Berstler J; Broad Institute of MIT and Harvard, Center for the Development of Therapeutics, Cambridge, MA 02142., Chai W; Janssen Research and Development, LLC., San Diego, CA 92121., Chang L; Janssen Research and Development, LLC., San Diego, CA 92121., Chung M; Janssen Research and Development, LLC., San Diego, CA 92121., Coe K; Janssen Research and Development, LLC., San Diego, CA 92121., Collins B; Janssen Research and Development, LLC., San Diego, CA 92121., Finley M; Janssen Research and Development, LLC., Spring House, PA 19477., Guletsky A; Broad Institute of MIT and Harvard, Center for the Development of Therapeutics, Cambridge, MA 02142., Lemke CT; Broad Institute of MIT and Harvard, Center for the Development of Therapeutics, Cambridge, MA 02142., Mak PA; Janssen Research and Development, LLC., San Diego, CA 92121., Mathur A; Janssen Research and Development, LLC., Spring House, PA 19477., Mercado-Marin EV; Janssen Research and Development, LLC., San Diego, CA 92121., Metkar S; Broad Institute of MIT and Harvard, Center for the Development of Therapeutics, Cambridge, MA 02142., Raymond DD; Broad Institute of MIT and Harvard, Center for the Development of Therapeutics, Cambridge, MA 02142., Rives ML; Janssen Research and Development, LLC., San Diego, CA 92121., Rizzolio M; Janssen Research and Development, LLC., San Diego, CA 92121., Shaffer PL; Janssen Research and Development, LLC., Spring House, PA 19477., Smith R; Janssen Research and Development, LLC., San Diego, CA 92121., Smith J; Janssen Research and Development, LLC., San Diego, CA 92121., Steele R; Janssen Research and Development, LLC., Spring House, PA 19477., Steffens H; Janssen Research and Development, LLC., San Diego, CA 92121., Suarez J; Janssen Research and Development, LLC., Spring House, PA 19477., Tian G; Janssen Research and Development, LLC., Spring House, PA 19477., Majewski N; Janssen Research and Development, LLC., Spring House, PA 19477., Volak LP; Janssen Research and Development, LLC., San Diego, CA 92121., Wei J; Janssen Research and Development, LLC., San Diego, CA 92121., Desai PT; Janssen Research and Development, LLC., Spring House, PA 19477., Ong LL; Janssen Research and Development, LLC., Spring House, PA 19477., Koudriakova T; Janssen Research and Development, LLC., San Diego, CA 92121., Goldberg SD; Janssen Research and Development, LLC., San Diego, CA 92121., Hirst G; Janssen Research and Development, LLC., San Diego, CA 92121., Kaushik VK; Broad Institute of MIT and Harvard, Center for the Development of Therapeutics, Cambridge, MA 02142., Ort T; Janssen Research and Development, LLC., Spring House, PA 19477., Seth N; Janssen Research and Development, LLC., Spring House, PA 19477., Graham DB; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114.; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114.; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142., Plevy S; Janssen Research and Development, LLC., Spring House, PA 19477., Venable JD; Janssen Research and Development, LLC., San Diego, CA 92121., Xavier RJ; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114.; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114.; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142., Towne JE; Janssen Research and Development, LLC., San Diego, CA 92121. |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jan 02; Vol. 121 (1), pp. e2307086120. Date of Electronic Publication: 2023 Dec 26. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | Protein Serine-Threonine Kinases*/metabolism , Cyclic AMP Response Element-Binding Protein*/metabolism, Mice ; Humans ; Animals ; Cytokines ; Inflammation/drug therapy ; Protein Isoforms ; Anti-Inflammatory Agents/pharmacology ; Immunity, Innate ; Transcription Factors |
| مستخلص: | 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. Competing Interests: Competing interests statement:The authors’ employment information at the time of data generation are marked in the “Author affiliations” section. H.B., T.B.S., M.T., M.S., G.B., W.C., L.C, De M.C., K.C., B.C., M.F., A.G., P.A.M., A.M., E.V.M.-M., M.-L.R., M.R., P.L.S., R. Smith, J. Smith, R. Steele, H.S., J. Suarez, G.T., N.M., L.P.V., J.W., P.T.D., L.L.O., T.K., S.D.G., G.H., T.O., N.S., S.P., J.D.V., J.E.T. are current or former employees of Janssen Research & Development, LLC, and employees may own stock/stock options in Johnson & Johnson, of which Janssen Research & Development, LLC is a subsidiary. R.J.X. is co-founder of Jnana Therapeutics and Celsius Therapeutics, scientific advisory board member at Nestlé and Magnet BioMedicine, board director at MoonLake Immunotherapeutics; these organizations had no roles in this study. G.B., W.C., De M.C., S.D.G., G.H., V.K.K., E.V.M.-M., D.D.R., H.S., M.S., R. Smith, T.B.S., M.T., J.D.V., J.W., and R.J.X. are named as inventors on the PCT patent application “Small Molecule Inhibitors of Salt Inducible Kinases”, published as WO 2022/165529, and N.M., R.J.X., T.B.S., G.T., and H.B. are named inventors on the PCT patent application “Materials and Methods for Differentiating CREB Regulated Transcription Coactivator 3”, published as WO 2022/260995. |
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| معلومات مُعتمدة: | P30 DK043351 United States DK NIDDK NIH HHS |
| فهرسة مساهمة: | Keywords: immunological disorders; inflammatory bowel disease; kinase inhibitors; medicinal chemistry; structure-based drug design |
| المشرفين على المادة: | EC 2.7.11.1 (Protein Serine-Threonine Kinases) 0 (Cyclic AMP Response Element-Binding Protein) 0 (Cytokines) 0 (Protein Isoforms) 0 (Anti-Inflammatory Agents) EC 2.7.11.1 (SIK1 protein, human) 0 (CRTC3 protein, mouse) 0 (Transcription Factors) |
| تواريخ الأحداث: | Date Created: 20231226 Date Completed: 20231228 Latest Revision: 20240913 |
| رمز التحديث: | 20240913 |
| مُعرف محوري في PubMed: | PMC10769863 |
| DOI: | 10.1073/pnas.2307086120 |
| PMID: | 38147543 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
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| DOI: | 10.1073/pnas.2307086120 |