title: Identification and characterization of small molecule antagonists of pRb inactivation by viral oncoproteins.
abstract: The retinoblastoma protein pRb is essential for regulating many cellular activities through its binding and inhibition of E2F transcription activators, and pRb inactivation leads to many cancers. pRb activity can be perturbed by viral oncoproteins including human papillomavirus (HPV) that share an LxCxE motif. Because there are no treatments for existing HPV infection leading to nearly all cervical cancers and other cancers to a lesser extent, we screened for compounds that inhibit the ability of HPV-E7 to disrupt pRb/E2F complexes. This lead to the identification of thiadiazolidinedione compounds that bind to pRb with mid-high nanomolar dissociation constants, are competitive with the binding of viral oncoproteins containing an LxCxE motif, and are selectively cytotoxic in HPV-positive cells alone and in mice. These inhibitors provide a promising scaffold for the development of therapies to treat HPV-mediated pathologies.
authors.affiliation: Program in Gene Expression and Regulation, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Fera
authors.forename: David C
authors.initials: DC
authors.lastname: Schultz
authors.forename: Santosh
authors.initials: S
authors.lastname: Hodawadekar
authors.forename: Melvin
authors.initials: M
authors.lastname: Reichman
authors.forename: Preston Scott
authors.initials: PS
authors.lastname: Donover
authors.forename: Jason
authors.initials: J
authors.lastname: Melvin
authors.forename: Scott
authors.initials: S
authors.lastname: Troutman
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kissil
authors.forename: Donna M
authors.initials: DM
authors.lastname: Huryn
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D050684:E2F Transcription Factors / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D027383:Papillomaviridae / Q000187:drug effects / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016415:Sequence Alignment; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D050684:E2F Transcription Factors; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein; D013830:Thiadiazoles