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
  • 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.
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