Small molecule scaffolds that disrupt the Rev1-CT/RIR protein-protein interaction

Zuleyha Ozen; Radha C Dash; Kaitlyn R McCarthy; Samantha A Chow; Alessandro A Rizzo; Dmitry M Korzhnev; M Kyle Hadden

doi:10.1016/j.bmc.2018.07.029

Small molecule scaffolds that disrupt the Rev1-CT/RIR protein-protein interaction

Bioorg Med Chem. 2018 Aug 7;26(14):4301-4309. doi: 10.1016/j.bmc.2018.07.029. Epub 2018 Jul 19.

Authors

Zuleyha Ozen¹, Radha C Dash¹, Kaitlyn R McCarthy¹, Samantha A Chow¹, Alessandro A Rizzo¹, Dmitry M Korzhnev², M Kyle Hadden³

Affiliations

¹ Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Storrs, CT 06269, USA.
² Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT 06030, USA.
³ Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Storrs, CT 06269, USA. Electronic address: kyle.hadden@uconn.edu.

PMID: 30037752
DOI: 10.1016/j.bmc.2018.07.029

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.

Keywords: Cancer; Protein-protein interaction; Rev1; Translesion synthesis.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Nuclear Proteins / antagonists & inhibitors*
Nuclear Proteins / metabolism
Nucleotidyltransferases / antagonists & inhibitors*
Nucleotidyltransferases / metabolism
Protein Binding / drug effects
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship
Thiophenes / chemical synthesis
Thiophenes / chemistry
Thiophenes / pharmacology*

Substances

Antineoplastic Agents
Nuclear Proteins
Small Molecule Libraries
Thiophenes
Nucleotidyltransferases
REV1 protein, human