PDF(Pubmed)
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.
摘要：
盐诱导型激酶(SIK)1-3是先天性免疫激活期间促炎性细胞因子应答与抗炎细胞因子应答的关键调节剂。缺乏适合重复的高度SIK家族或SIK同工型选择性抑制剂，口服给药限制了对体内抑制炎症的最佳SIK同工型选择性谱的研究.为了克服这一挑战，我们设计了一种基于结构的设计策略,用于开发有效的SIK抑制剂,该抑制剂通过结合SIK催化位点的两个差异特征而对其他激酶具有高度选择性.这项工作产生了SIK1/2选择性探针，该探针抑制关键的细胞内近端信号传导事件，包括减少SIK底物cAMP反应元件结合蛋白（CREB）调节的转录共激活因子3（CRTC3）的磷酸化，如内部产生的磷酸Ser329-CRTC3特异性抗体所检测到的。这些抑制剂还抑制促炎细胞因子的产生,同时在激活的人和鼠骨髓细胞中以及在脂多糖攻击后的小鼠中诱导抗炎白介素-10。这些化合物的口服给药改善了鼠结肠炎模型中的疾病。这些发现定义了一种产生高选择性SIK1/2抑制剂的方法，并确定靶向这些同种型可能是抑制病理性炎症的有用策略。
