Docking-Based Virtual Screening Identifies a Small-Molecule Inhibitor of the Translesion Synthesis REV7/REV3...

REV7 is an adaptor protein that mediates protein-protein interactions (PPIs) in DNA damage response and cell cycle control. REV7 functions as a subunit of the translesion synthesis (TLS) DNA polymerase POLζ, which is involved in the replicative bypass of DNA lesions. REV7 is also a component of the shieldin complex, which mediates the choice of pathway for DNA double-stranded break (DSB) repair. TLS promotes cancer cell survival after DNA damage and serves as a mechanism through which cancers develop acquired chemoresistance. DSB repair helps cancers mitigate DNA breaks induced by radiation; therefore, inhibition of REV7 PPIs has emerged as a therapeutic strategy. We performed a docking-based virtual screen to identify compounds predicted to disrupt PPIs between REV7 and the REV7-binding motifs (RBMs) found in the REV3 subunit of POLζ (TLS) and the SHLD3 subunit of shieldin (DSB repair). Biochemical analysis of a promising hit compound and several analogues demonstrated the ability of this scaffold to disrupt the REV7/RBM_REV3 PPI. Several REV7 inhibitors sensitize human cancer cells to radiation treatment, identifying these compounds as a new class of TLS and DSB-repair targeted anticancer drugs with potential as adjuvant therapies to improve the efficacy of genotoxic cancer therapies.