title: Identification of new SUMO activating enzyme 1 inhibitors using virtual screening and scaffold hopping.
abstract: Sumoylation involves the enzymatic conjugation of small ubiquitin-like modifier (SUMO) protein to their substrate proteins. Sumoylation is not only crucial for maintaining normal cellular physiology but also implicated in the development of several diseases including cancer. SUMO E1, the first protein in sumoylation pathway is of particular significance due to its confirmed role in tumorogenesis. However, notwithstanding its role as potential drug target, only a few small molecule inhibitors of SUMO E1 have been identified. Here, we report the identification of pyrazole and thiazole urea containing compounds as inhibitors of SUMO E1. We have utilized 3D-shape matching, electrostatic potential similarity evaluations and molecular docking to scaffold hop from previously known aryl urea scaffold with SUMO E1 activity to thiazole and pyrazole urea based scaffolds. These two classes of compounds were found to have moderate SUMO E1 inhibitory activity and can be used as starting points for the development of highly potent lead compounds against cancer.
authors.affiliation: Structural Bioinformatics Team, Division of Structural and Synthetic Biology, Center for Life Science Technologies, RIKEN, 1-7-22 Suehiro, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Chemical Genetics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.affiliation: Chemical Genetics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Mikako
authors.initials: M
authors.lastname: Hirohama
authors.affiliation: Chemical Genetics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Japan Agency for Medical Research and Development, AMED-CREST, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Structural Bioinformatics Team, Division of Structural and Synthetic Biology, Center for Life Science Technologies, RIKEN, 1-7-22 Suehiro, Yokohama, Kanagawa 230-0045, Japan. Electronic address: kamzhang@riken.jp.
authors.forename: Kam Y J
authors.initials: KY
authors.lastname: Zhang
mesh_terms: D001665:Binding Sites; D006801:Humans; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry; D025841:Small Ubiquitin-Related Modifier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry; D014508:Urea / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D011720:Pyrazoles; D025841:Small Ubiquitin-Related Modifier Proteins; D013844:Thiazoles; D014508:Urea
keywords: SUMO; SUMO E1 inhibitor; Scaffold hopping; Sumoylation; Virtual screening