鉴定高度选择性的SIK1/2抑制剂,调节先天免疫激活并抑制肠道炎症
Holger Babbe1, Thomas B Sundberg2, Mark Tichenor3
1Janssen Research and Development, LLC., Spring House, PA 19477.
针对盐诱导性激酶 (SIK) 1和2的新抑制剂提供了一种选择性的方法来抑制炎症. 这些化合物的口服有效地减少了在临床前模型中的炎症反应.
科学领域:
- 免疫学 免疫学 免疫学
- 药理学 药理学是指药理学的学科.
- 生物化学 生物化学
背景情况:
- 盐诱导激酶 (SIK) 1-3调节先天免疫反应,平衡亲和抗炎细胞因子的产生.
- 选择性SIK抑制剂用于口服的有限可用性阻碍了对异形特异性抗炎策略的体内研究.
研究的目的:
- 通过基于结构的设计方法开发强效和高度SIK异型选择性抑制剂.
- 调查针对SIK1/2的治疗潜力,以抑制病理性炎症.
主要方法:
- 基于结构的药物设计,以创建对SIK催化部位有选择性的SIK抑制剂.
- 使用-Ser329-CRTC3特异性抗体检测抑制SIK基质酸化.
- 将化合物口服给人类和小鼠骨髓状细胞以及体内小鼠模型.
主要成果:
- 开发了SIK1/2-选择性抑制剂,可以减少SIK基质CRTC3.3的酸化.
- 抑制剂抑制了促炎性细胞因子的产生,并在髓质细胞和小鼠中诱导了抗炎性IL-10.
- 在小鼠结肠炎模型中,口服改善了疾病.
结论:
- 一个基于结构的策略成功产生了高度选择性的SIK1/2抑制剂.
- 向SIK1/2异型是一种有前途的治疗策略,用于管理炎症性疾病.
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