除了泛素-蛋白酶体系统外，自噬是一种高效且有吸引力的蛋白质降解途径。本文报道了与CDK9抑制剂SNS-032连接的香豆素类似物的系统优化，该类物质可能同时与细胞周期依赖性激酶9 (CDK9) 和微管相关蛋白1轻链3β(LC3B)结合，从而导致有选择性地降解目标CDK9/细胞周期依赖性激酶T1，并且与THAL-SNS-032这种PROTAC降解剂不同。进一步的机制研究发现了一个自噬-溶酶体途径，其中这些降解剂可能与CDK9和LC3B形成三元复合物。此外，降解剂10 在体内显示出抗肿瘤功效。我们的研究优化了一种有效的LC3B招募物，并证明了自噬系结化合物 (ATTECs) 的可行性，这些化合物可以应用于降解各种细胞内致病蛋白质来治疗相关疾病。

Autophagy is an efficient and attractive protein degradation pathway in addition to the ubiquitin-proteasome system. Herein, systematic optimization of coumarin analogs linked with the CDK9 inhibitor SNS-032 is reported that may bind to cyclin-dependent kinase 9 (CDK9) and microtubule-associated protein 1 light chain 3 beta (LC3B) simultaneously, which leads to the selective autophagic degradation of targeted CDK9/cyclin T1 and is different from the PROTAC degrader THAL-SNS-032. Further mechanism studies revealed an autophagy-lysosome pathway, where the degraders possibly formed a ternary complex with CDK9 and LC3B. In addition, degrader 10 showed antitumor efficacy in vivo. Our work optimized a potent LC3B recruiter and demonstrated the feasibility of autophagy-tethering compounds (ATTECs), which could be applied for the degradation of diverse intracellular pathogenic proteins to treat related diseases.