Identification of the first small-molecule inhibitor of the REV7 DNA repair protein interaction

Abstract

DNA interstrand crosslink (ICL) repair (ICLR) has been implicated in the resistance of cancer cells to ICL-inducing chemotherapeutic agents. Despite the clinical significance of ICL-inducing chemotherapy, few studies have focused on developing small-molecule inhibitors for ICLR. The mammalian DNA polymerase ζ, which comprises the catalytic subunit REV3L and the non-catalytic subunit REV7, is essential for ICLR. To identify small-molecule compounds that are mechanistically capable of inhibiting ICLR by targeting REV7, high-throughput screening and structure-activity relationship (SAR) analysis were performed. Compound 1 was identified as an inhibitor of the interaction of REV7 with the REV7-binding sequence of REV3L. Compound 7 (an optimized analog of compound 1) bound directly to REV7 in nuclear magnetic resonance analyses, and inhibited the reactivation of a reporter plasmid containing an ICL in between the promoter and reporter regions. The normalized clonogenic survival of HeLa cells treated with cisplatin and compound 7 was lower than that for cells treated with cisplatin only. These findings indicate that a small-molecule inhibitor of the REV7/REV3L interaction can chemosensitize cells by inhibiting ICLR.

Structural insight into inhibition of REV7 protein interaction revealed by docking, molecular dynamics and MM/PBSA studies

“…2), an inhibitor of the interaction of REV7 with the REV7-binding sequence of REV3L. 19 In the thermal shi assay, compound 1 showed a clear shi in the denaturation point of the His-REV7(R124A)/REV3L(1847-1898) complex, suggesting that compound 1 exchanged with REV3L(1847-1898) in the complex but was not nonspecically bound on the complex. The pull-down assay also indicated that both compound 1 and REV3L(1875-1895) can exchange with the biotin-AviTa-gREV3L(1846-1898) in the complex, resulting in the release of His-REV7(R124A) from the beads.…”

Fanconi anemia pathway as a prospective target for cancer intervention

“…DNA binding REV7 specific compounds [175][176][177][178][179][180] FANCW/RFWD3 6CVZ E3 FANCQ/XPF 1Z00, 2A1J, 2AQ0, 2KN7, 2MUT DNA incision [181][182][183][184][185]…”

Replication Fork Remodeling and Therapy Escape in DNA Damage Response-Deficient Cancers

“…Moreover, while several small molecule inhibitors of TLS components have been discovered, none of them were shown to have activity in vivo (204). Examples comprise previously described selective inhibitors of REV7 (205), oxetanocin derivatives inhibiting Pol η (206), or small molecule compounds blocking the interaction between components of the Pol ζ complex (207). One example of a small inhibitor shown to be active in vivo is a recently described molecule JH-RE-06.…”