J Med Chem. 2020 Mar 12;63(5):1892-1907. doi: 10.1021/acs.jmedchem.9b01318. Epub 2019 Oct 9.
The AAA+ ATPase, p97, also referred to as VCP, plays an essential role in cellular homeostasis by regulating endoplasmic reticulum-associated degradation (ERAD), mitochondrial-associated degradation (MAD), chromatin-associated degradation, autophagy, and endosomal trafficking. Mutations in p97 have been linked to a number of neurodegenerative diseases, and overexpression of wild type p97 is observed in numerous cancers. Furthermore, p97 activity has been shown to be essential for the replication of certain viruses, including poliovirus, herpes simplex virus (HSV), cytomegalovirus (CMV), and influenza. Taken together, these observations highlight the potential for targeting p97 as a therapeutic approach in neurodegeneration, cancer, and certain infectious diseases. This Perspective reviews recent advances in the discovery of small molecule inhibitors of p97, their optimization and characterization, and therapeutic potential.
AAA+ ATPase p97，也称为 VCP，通过调节内质网相关降解（ERAD）、线粒体相关降解（MAD）、染色质相关降解、自噬和内体运输，在细胞内稳态中发挥着重要作用。p97 的突变与许多神经退行性疾病有关，并且在许多癌症中观察到野生型 p97 的过表达。此外，p97 的活性已被证明对某些病毒（包括脊髓灰质炎病毒、单纯疱疹病毒、巨细胞病毒和流感病毒）的复制至关重要。综上所述，这些观察结果突出了将 p97 作为神经退行性疾病、癌症和某些传染病的治疗方法的潜力。本观点综述了 p97 小分子抑制剂的发现、优化和表征以及治疗潜力方面的最新进展。
