title: An optimized RAD51 inhibitor that disrupts homologous recombination without requiring Michael acceptor reactivity.
abstract: Homologous recombination (HR) is an essential process in cells that provides repair of DNA double-strand breaks and lesions that block DNA replication. RAD51 is an evolutionarily conserved protein that is central to HR. Overexpression of RAD51 protein is common in cancer cells and represents a potential therapeutic target in oncology. We previously described a chemical inhibitor of RAD51, called RI-1 (referred to as compound 1 in this report). The chloromaleimide group of this compound is thought to act as a Michael acceptor and react with the thiol group on C319 of RAD51, using a conjugate addition-elimination mechanism. In order to reduce the likelihood of off-target effects and to improve compound stability in biological systems, we developed an analogue of compound 1 that lacks maleimide-based reactivity but retains RAD51 inhibitory activity. This compound, 1-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)-4-morpholino-1H-pyrrole-2,5-dione, named RI-2 (referred to as compound 7a in this report), appears to bind reversibly to the same site on the RAD51 protein as does compound 1. Like compound 1, compound 7a specifically inhibits HR repair in human cells.
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, 5758 S. Maryland Avenue, Chicago, Illinois 60637, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Budke
authors.forename: Jay H
authors.initials: JH
authors.lastname: Kalin
authors.forename: Michal
authors.initials: M
authors.lastname: Pawlowski
authors.forename: Anna S
authors.initials: AS
authors.lastname: Zelivianskaia
authors.forename: Megan
authors.initials: M
authors.lastname: Wu
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Philip P
authors.initials: PP
authors.lastname: Connell
mesh_terms: D001665:Binding Sites; D004247:DNA / Q000737:chemistry; D004260:DNA Repair / Q000187:drug effects; D057809:HEK293 Cells; D059765:Homologous Recombination / Q000187:drug effects*; D006801:Humans; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011758:Pyrroles / Q000737:chemistry; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C579728:1-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)-4-morpholino-1H-pyrrole-2,5-dione; C576134:3-chloro-1-(3,4-dichlorophenyl)-4-(4-morpholinyl)-1H-pyrrole-2,5-dione; D008301:Maleimides; D009025:Morpholines; D011758:Pyrroles; D004247:DNA; D051135:Rad51 Recombinase