title: Design of high-throughput screening assays and identification of a SUMO1-specific small molecule chemotype targeting the SUMO-interacting motif-binding surface.
abstract: Protein-protein interactions are generally challenging to target by small molecules. To address the challenge, we have used a multidisciplinary approach to identify small-molecule disruptors of protein-protein interactions that are mediated by SUMO (small ubiquitin-like modifier) proteins. SUMO modifications have emerged as a target with importance in treating cancer, neurodegenerative disorders, and viral infections. It has been shown that inhibiting SUMO-mediated protein-protein interactions can sensitize cancer cells to chemotherapy and radiation. We have developed highly sensitive assays using time-resolved fluorescence resonance energy transfer (TR-FRET) and fluorescence polarization (FP) that were used for high-throughput screening (HTS) to identify inhibitors for SUMO-dependent protein-protein interactions. Using these assays, we have identified a nonpeptidomimetic small molecule chemotype that binds to SUMO1 but not SUMO2 or 3. NMR chemical shift perturbation studies have shown that the compounds of this chemotype bind to the SUMO1 surface required for protein-protein interaction, despite the high sequence similarity of SUMO1 and SUMO2 and 3 at this surface.
authors.affiliation: †Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California 91010, United States.
authors.forename: Aileen Y
authors.initials: AY
authors.lastname: Alontaga
authors.affiliation: †Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California 91010, United States.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Li
authors.affiliation: †Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California 91010, United States.
authors.forename: Chih-Hong
authors.initials: CH
authors.lastname: Chen
authors.affiliation: ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Institute, La Jolla, California 92037, United States.
authors.forename: Chen-Ting
authors.initials: CT
authors.lastname: Ma
authors.affiliation: §Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Institute at Lake Nona, Orlando, Florida 32827, United States.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Malany
authors.affiliation: §Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Institute at Lake Nona, Orlando, Florida 32827, United States.
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Key
authors.affiliation: ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Institute, La Jolla, California 92037, United States.
authors.forename: Eduard
authors.initials: E
authors.lastname: Sergienko
authors.affiliation: ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Institute, La Jolla, California 92037, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Sun
authors.affiliation: ∥University of Kansas Specialized Chemistry Center, Lawrence, Kansas 66049, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Whipple
authors.affiliation: ∥University of Kansas Specialized Chemistry Center, Lawrence, Kansas 66049, United States.
authors.forename: Daljit S
authors.initials: DS
authors.lastname: Matharu
authors.affiliation: †Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California 91010, United States.
authors.forename: Baozong
authors.initials: B
authors.lastname: Li
authors.affiliation: †Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California 91010, United States.
authors.forename: Ramir
authors.initials: R
authors.lastname: Vega
authors.affiliation: †Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California 91010, United States.
authors.forename: Yi-Jia
authors.initials: YJ
authors.lastname: Li
authors.affiliation: ∥University of Kansas Specialized Chemistry Center, Lawrence, Kansas 66049, United States.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Schoenen
authors.affiliation: ∥University of Kansas Specialized Chemistry Center, Lawrence, Kansas 66049, United States.
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
authors.affiliation: ‡Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Institute, La Jolla, California 92037, United States.
authors.forename: Thomas D Y
authors.initials: TD
authors.lastname: Chung
authors.affiliation: †Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California 91010, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D031541:Fluorescence Resonance Energy Transfer; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D025841:Small Ubiquitin-Related Modifier Proteins / Q000737:chemistry*
chemical_list: D008024:Ligands; D025841:Small Ubiquitin-Related Modifier Proteins
keywords: SUMO-interacting motif (SIM); TR-FRET; fluorescence polarization; small ubiquitin-like modifier (SUMO)