Small molecule scaffolds that disrupt the Rev1-CT/RIR protein-protein interaction. Issue 14 (7th August 2018)

• Record Type: Journal Article
• Authors: Ozen, Zuleyha; Dash, Radha C.; McCarthy, Kaitlyn R.; Chow, Samantha A.; Rizzo, Alessandro A.; Korzhnev, Dmitry M.; Hadden, M. Kyle
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 14(2018)
• Page Start: 4301
• Page End: 4309
• Publication Date: 2018-08-07
• Subjects: Translesion synthesis -- Cancer -- Rev1 -- Protein-protein interaction; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.07.029
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Translesion synthesis (TLS) is a DNA damage tolerance mechanism that allows replicative bypass of DNA lesions, including DNA adducts formed by cancer chemotherapeutics. Previous studies demonstrated that suppression of TLS can increase sensitivity of cancer cells to first-line chemotherapeutics and decrease mutagenesis linked to the onset of chemoresistance, marking the TLS pathway as an emerging therapeutic target. TLS is mediated by a heteroprotein complex consisting of specialized DNA polymerases, including the Y-family DNA polymerase Rev1. Previously, we developed a screening assay to identify the first small molecules that disrupt the protein–protein interaction between the C-terminal domain of Rev1 (Rev1-CT) and the Rev1-interacting region (RIR) present in multiple DNA polymerases involved in TLS. Herein we report additional hit scaffolds that inhibit this key TLS PPI. In addition, through a series of biochemical, computational, and cellular studies we have identified preliminary structure–activity relationships and determined initial pharmacokinetic parameters for our original hits.