Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:121 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 121(2024), 1 vom: 02. Jan., Seite e2307086120 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Babbe, Holger [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 28.12.2023 Date Revised 08.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2307086120 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366382179 |
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| 245 | 1 | 0 | |a Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation |
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| 500 | |a Date Completed 28.12.2023 | ||
| 500 | |a Date Revised 08.01.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a immunological disorders | |
| 650 | 4 | |a inflammatory bowel disease | |
| 650 | 4 | |a kinase inhibitors | |
| 650 | 4 | |a medicinal chemistry | |
| 650 | 4 | |a structure-based drug design | |
| 650 | 7 | |a Protein Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Cyclic AMP Response Element-Binding Protein |2 NLM | |
| 650 | 7 | |a Cytokines |2 NLM | |
| 650 | 7 | |a Protein Isoforms |2 NLM | |
| 650 | 7 | |a Anti-Inflammatory Agents |2 NLM | |
| 650 | 7 | |a SIK1 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a CRTC3 protein, mouse |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 700 | 1 | |a Sundberg, Thomas B |e verfasserin |4 aut | |
| 700 | 1 | |a Tichenor, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Seierstad, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Bacani, Genesis |e verfasserin |4 aut | |
| 700 | 1 | |a Berstler, James |e verfasserin |4 aut | |
| 700 | 1 | |a Chai, Wenying |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Leon |e verfasserin |4 aut | |
| 700 | 1 | |a Chung, De Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Coe, Kevin |e verfasserin |4 aut | |
| 700 | 1 | |a Collins, Bernard |e verfasserin |4 aut | |
| 700 | 1 | |a Finley, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Guletsky, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a Lemke, Christopher T |e verfasserin |4 aut | |
| 700 | 1 | |a Mak, Puiying A |e verfasserin |4 aut | |
| 700 | 1 | |a Mathur, Ashok |e verfasserin |4 aut | |
| 700 | 1 | |a Mercado-Marin, Eduardo V |e verfasserin |4 aut | |
| 700 | 1 | |a Metkar, Shailesh |e verfasserin |4 aut | |
| 700 | 1 | |a Raymond, Donald D |e verfasserin |4 aut | |
| 700 | 1 | |a Rives, Marie-Laure |e verfasserin |4 aut | |
| 700 | 1 | |a Rizzolio, Michele |e verfasserin |4 aut | |
| 700 | 1 | |a Shaffer, Paul L |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Russell |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Jacqueline |e verfasserin |4 aut | |
| 700 | 1 | |a Steele, Ruth |e verfasserin |4 aut | |
| 700 | 1 | |a Steffens, Helena |e verfasserin |4 aut | |
| 700 | 1 | |a Suarez, Javier |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Gaochao |e verfasserin |4 aut | |
| 700 | 1 | |a Majewski, Nathan |e verfasserin |4 aut | |
| 700 | 1 | |a Volak, Laurie P |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Jianmei |e verfasserin |4 aut | |
| 700 | 1 | |a Desai, Prerak T |e verfasserin |4 aut | |
| 700 | 1 | |a Ong, Luvena L |e verfasserin |4 aut | |
| 700 | 1 | |a Koudriakova, Tatiana |e verfasserin |4 aut | |
| 700 | 1 | |a Goldberg, Steven D |e verfasserin |4 aut | |
| 700 | 1 | |a Hirst, Gavin |e verfasserin |4 aut | |
| 700 | 1 | |a Kaushik, Virendar K |e verfasserin |4 aut | |
| 700 | 1 | |a Ort, Tatiana |e verfasserin |4 aut | |
| 700 | 1 | |a Seth, Nilufer |e verfasserin |4 aut | |
| 700 | 1 | |a Graham, Daniel B |e verfasserin |4 aut | |
| 700 | 1 | |a Plevy, Scott |e verfasserin |4 aut | |
| 700 | 1 | |a Venable, Jennifer D |e verfasserin |4 aut | |
| 700 | 1 | |a Xavier, Ramnik J |e verfasserin |4 aut | |
| 700 | 1 | |a Towne, Jennifer E |e verfasserin |4 aut | |
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