School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Department of Pharmacy, 920th Hospital of Joint Logistics Support Force, Kunming 650032, China.
J Med Chem. 2022 Jun 9;65(11):7619-7628. doi: 10.1021/acs.jmedchem.1c02001. Epub 2022 May 19.
Autophagosome-tethering compounds (ATTECs) are an emerging new technology in targeted protein degradation. However, effective tools and successful examples for autophagosome-tethering chimeras are still rather limited. Herein, ATTEC ispinesib was identified for the first time to be an effective warhead to design autophagosome-tethering chimeras. As a conceptual validation study, the first generation of autophagic degraders of nicotinamide phosphoribosyltransferase (NAMPT) were developed by connecting the NAMPT inhibitor and LC3-binding ispinesib through a flexible linker. In particular, compound significantly induced the degradation of NAMPT through the autophagy-lysosomal pathway, leading to excellent cellular antitumor potency. Ispinesib may have broad applications in the design of potent autophagosome-tethering chimeras.
自噬体连接化合物（ATTECs）是靶向蛋白降解领域的一项新兴新技术。然而，有效的工具和成功的自噬体连接嵌合体的例子仍然相当有限。本文首次发现 ATTEC 依维莫司是一种有效的弹头，可以用于设计自噬体连接嵌合体。作为概念验证研究，通过连接一个柔性接头，将烟酰胺磷酸核糖转移酶（NAMPT）的抑制剂和 LC3 结合的依维莫司，设计了第一代自噬降解物。特别是，化合物 通过自噬溶酶体途径显著诱导了 NAMPT 的降解，从而表现出优异的细胞抗肿瘤活性。依维莫司可能在设计有效的自噬体连接嵌合体方面具有广泛的应用。
