Max-Planck-Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.
Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 4a, 44227, Dortmund, Germany.
Angew Chem Int Ed Engl. 2017 Jul 3;56(28):8153-8157. doi: 10.1002/anie.201703738. Epub 2017 Jun 12.
Autophagy is a critical regulator of cellular homeostasis and metabolism. Interference with this process is considered a new approach for the treatment of disease, in particular cancer and neurological disorders. Therefore, novel small-molecule autophagy modulators are in high demand. We describe the discovery of autophinib, a potent autophagy inhibitor with a novel chemotype. Autophinib was identified by means of a phenotypic assay monitoring the formation of autophagy-induced puncta, indicating accumulation of the lipidated cytosolic protein LC3 on the autophagosomal membrane. Target identification and validation revealed that autophinib inhibits autophagy induced by starvation or rapamycin by targeting the lipid kinase VPS34.
自噬是细胞内稳态和代谢的关键调节因子。干扰这一过程被认为是治疗疾病的一种新方法，特别是癌症和神经紊乱。因此，新型小分子自噬调节剂的需求很高。我们描述了自噬抑制剂 autophinib 的发现，这是一种具有新型化学结构的强效自噬抑制剂。自噬抑制剂是通过监测自噬诱导的斑点形成的表型测定法鉴定出来的，这表明了脂化细胞质蛋白 LC3 在自噬体膜上的积累。靶标鉴定和验证表明，自噬抑制剂通过靶向脂质激酶 VPS34 抑制饥饿或雷帕霉素诱导的自噬。
