1区 · 综合性期刊
Article
作者: Towne, Jennifer E. ; Guletsky, Alexander ; Graham, Daniel B. ; Chang, Leon ; Mak, Puiying A. ; Suarez, Javier ; Ong, Luvena L. ; Desai, Prerak T. ; Steele, Ruth ; Finley, Michael ; Chai, Wenying ; Shaffer, Paul L. ; Sundberg, Thomas B. ; Goldberg, Steven D. ; Mercado-Marin, Eduardo V. ; Volak, Laurie P. ; Steffens, Helena ; Tichenor, Mark ; Collins, Bernard ; Metkar, Shailesh ; Babbe, Holger ; Rizzolio, Michele ; Smith, Russell ; Mathur, Ashok ; Wei, Jianmei ; Kaushik, Virendar K. ; Tian, Gaochao ; Lemke, Christopher T. ; Plevy, Scott ; Bacani, Genesis ; Raymond, Donald D. ; Seierstad, Mark ; Hirst, Gavin ; Venable, Jennifer D. ; Ort, Tatiana ; Xavier, Ramnik J. ; Koudriakova, Tatiana ; Majewski, Nathan ; Chung, De Michael ; Coe, Kevin ; Smith, Jacqueline ; Berstler, James ; Seth, Nilufer ; Rives, Marie-Laure
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.
