Red de Estudios Moleculares Avanzados, Instituto de Ecología A.C., Xalapa, Veracruz, México.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA.
Sci Rep. 2017 Mar 21;7:44912. doi: 10.1038/srep44912.
Valosin-containing protein (VCP/p97) ATPase (a.k.a. Cdc48) is a key member of the ER-associated protein degradation (ERAD) pathway. ERAD and VCP/p97 have been implicated in a multitude of human diseases, such as neurodegenerative diseases and cancer. Inhibition of VCP/p97 induces proteotoxic ER stress and cell death in cancer cells, making it an attractive target for cancer treatment. However, no drugs exist against this protein in the market. Repositioning of drugs towards new indications is an attractive alternative to the de novo drug development due to the potential for significantly shorter time to clinical translation. Here, we employed an integrative strategy for the repositioning of drugs as novel inhibitors of the VCP/p97 ATPase. We integrated structure-based virtual screening with the chemical genomics analysis of drug molecular signatures, and identified several candidate inhibitors of VCP/p97 ATPase. Importantly, experimental validation with cell-based and in vitro ATPase assays confirmed three (ebastine, astemizole and clotrimazole) out of seven tested candidates (~40% true hit rate) as direct inhibitors of VCP/p97 and ERAD. This study introduces an effective integrative strategy for drug repositioning, and identified new drugs against the VCP/p97/ERAD pathway in human diseases.
包含缬氨酸的蛋白 (VCP/p97) ATP 酶（又名 Cdc48）是内质网相关蛋白降解 (ERAD) 途径的关键成员。ERAD 和 VCP/p97 与多种人类疾病有关，如神经退行性疾病和癌症。抑制 VCP/p97 会在内质网应激和癌细胞死亡中诱导蛋白毒性，使其成为癌症治疗的有吸引力的靶点。然而，市场上没有针对这种蛋白质的药物。由于潜在的临床转化时间大大缩短，重新定位药物以用于新的适应症是一种有吸引力的新药开发替代方案。在这里，我们采用了一种综合策略，将药物重新定位为 VCP/p97 ATP 酶的新型抑制剂。我们将基于结构的虚拟筛选与药物分子特征的化学基因组学分析相结合，鉴定出几种 VCP/p97 ATP 酶的候选抑制剂。重要的是，基于细胞的和体外 ATP 酶测定的实验验证证实了七种测试候选物中的三种（依巴斯汀、阿司咪唑和克霉唑）（约 40%的真实命中率）为 VCP/p97 和 ERAD 的直接抑制剂。这项研究介绍了一种有效的药物重新定位综合策略，并确定了针对人类疾病中 VCP/p97/ERAD 途径的新药物。
