2. Academic Validation
  3. Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation

Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation

  • Proc Natl Acad Sci U S A. 2024 Jan 2;121(1):e2307086120. doi: 10.1073/pnas.2307086120.
Holger Babbe # 1,  Thomas B Sundberg # 2,  Mark Tichenor # 3,  Mark Seierstad 3,  Genesis Bacani 3,  James Berstler 2,  Wenying Chai 3,  Leon Chang 3,  De Michael Chung 3,  Kevin Coe 3,  Bernard Collins 3,  Michael Finley 1,  Alexander Guletsky 2,  Christopher T Lemke 2,  Puiying A Mak 3,  Ashok Mathur 1,  Eduardo V Mercado-Marin 3,  Shailesh Metkar 2,  Donald D Raymond 2,  Marie-Laure Rives 3,  Michele Rizzolio 3,  Paul L Shaffer 1,  Russell Smith 3,  Jacqueline Smith 3,  Ruth Steele 1,  Helena Steffens 3,  Javier Suarez 1,  Gaochao Tian 1,  Nathan Majewski 1,  Laurie P Volak 3,  Jianmei Wei 3,  Prerak T Desai 1,  Luvena L Ong 1,  Tatiana Koudriakova 3,  Steven D Goldberg 3,  Gavin Hirst 3,  Virendar K Kaushik 2,  Tatiana Ort 1,  Nilufer Seth 1,  Daniel B Graham 4 5 6,  Scott Plevy 1,  Jennifer D Venable 3,  Ramnik J Xavier 4 5 6,  Jennifer E Towne 3
Affiliations

Affiliations

  • 1 Janssen Research and Development, LLC., Spring House, PA 19477.
  • 2 Broad Institute of MIT and Harvard, Center for the Development of Therapeutics, Cambridge, MA 02142.
  • 3 Janssen Research and Development, LLC., San Diego, CA 92121.
  • 4 Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114.
  • 5 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114.
  • 6 Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142.
  • # Contributed equally.
PMID: 38147543 DOI: 10.1073/pnas.2307086120
Abstract

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.

Keywords

immunological disorders; inflammatory bowel disease; kinase inhibitors; medicinal chemistry; structure-based drug design.

Figures
Products