Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
EMBO Rep. 2022 Jun 7;23(6):e53932. doi: 10.15252/embr.202153932. Epub 2022 Apr 11.
Aberrant activation of stimulator of interferon genes (STING) is tightly associated with multiple types of disease, including cancer, infection, and autoimmune diseases. However, the development of STING modulators for the therapy of STING-related diseases is still an unmet clinical need. We employed a high-throughput screening approach based on the interaction of small-molecule chemical compounds with recombinant STING protein to identify functional STING modulators. Intriguingly, the cyclin-dependent protein kinase (CDK) inhibitor Palbociclib was found to directly bind STING and inhibit its activation in both mouse and human cells. Mechanistically, Palbociclib targets Y167 of STING to block its dimerization, its binding with cyclic dinucleotides, and its trafficking. Importantly, Palbociclib alleviates autoimmune disease features induced by dextran sulphate sodium or genetic ablation of three prime repair exonuclease 1 (Trex1) in mice in a STING-dependent manner. Our work identifies Palbociclib as a novel pharmacological inhibitor of STING that abrogates its homodimerization and provides a basis for the fast repurposing of this Food and Drug Administration-approved drug for the therapy of autoinflammatory diseases.
干扰素基因刺激物（STING）的异常激活与多种疾病密切相关，包括癌症、感染和自身免疫性疾病。然而，STING 调节剂的开发用于治疗 STING 相关疾病仍然是未满足的临床需求。我们采用了一种基于小分子化合物与重组 STING 蛋白相互作用的高通量筛选方法来鉴定功能性 STING 调节剂。有趣的是，细胞周期蛋白依赖性激酶（CDK）抑制剂 Palbociclib 被发现可直接与 STING 结合并抑制其在小鼠和人细胞中的激活。在机制上，Palbociclib 靶向 STING 的 Y167 以阻止其二聚化、与环二核苷酸的结合及其运输。重要的是，Palbociclib 以 STING 依赖的方式减轻葡聚糖硫酸钠或三引物修复外切酶 1（Trex1）基因缺失诱导的小鼠自身免疫性疾病特征。我们的工作确定 Palbociclib 是一种新型 STING 药理学抑制剂，可阻断其同源二聚化，并为快速重新利用这种经美国食品和药物管理局批准的药物治疗自身炎症性疾病提供了依据。
