A structure- and chemical genomics-based approach for repositioning of drugs against VCP/p97 ATPase.
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.
Red de Estudios Moleculares Avanzados, Instituto de Ecología A.C., Xalapa, Veracruz, México.
Aldo
A
Segura-Cabrera
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA.
Reshmi
R
Tripathi
Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA.
Xiaoyi
X
Zhang
Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA.
Lin
L
Gui
Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA.
Tsui-Fen
TF
Chou
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH, USA.
Kakajan
K
Komurov
D000494:Allosteric Regulation; D001665:Binding Sites; D055808:Drug Discovery / Q000379:methods; D058492:Drug Repositioning; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D023281:Genomics / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D000074405:Valosin Containing Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics
D004791:Enzyme Inhibitors; D000074405:Valosin Containing Protein