A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy.

Abstract

Intrinsic and acquired drug resistance and induction of secondary malignancies limit successful chemotherapy. Because mutagenic translesion synthesis (TLS) contributes to chemoresistance as well as treatment-induced mutations, targeting TLS is an attractive avenue for improving chemotherapeutics. However, development of small molecules with high specificity and in vivo efficacy for mutagenic TLS has been challenging. Here, we report the discovery of a small-molecule inhibitor, JH-RE-06, that disrupts mutagenic TLS by preventing recruitment of mutagenic POL ζ. Remarkably, JH-RE-06 targets a nearly featureless surface of REV1 that interacts with the REV7 subunit of POL ζ. Binding of JH-RE-06 induces REV1 dimerization, which blocks the REV1-REV7 interaction and POL ζ recruitment. JH-RE-06 inhibits mutagenic TLS and enhances cisplatin-induced toxicity in cultured human and mouse cell lines. Co-administration of JH-RE-06 with cisplatin suppresses the growth of xenograft human melanomas in mice, establishing a framework for developing TLS inhibitors as a novel class of chemotherapy adjuvants.

• Authors: Jessica L Wojtaszek, Nimrat Chatterjee, Javaria Najeeb, Azucena Ramos, Minhee Lee, Ke Bian, Jenny Y Xue, Benjamin A Fenton, Hyeri Park, Deyu Li, Michael T Hemann, Jiyong Hong, Graham C Walker, Pei Zhou
• Journal: Cell (Cell) Vol. 178 Issue 1 Pg. 152-159.e11 (06 27 2019) ISSN: 1097-4172 [Electronic] United States
• PMID: 31178121 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• 1,4-dihydroquinoline
• Antineoplastic Agents
• MAD2L2 protein, human
• Mad2 Proteins
• Mad2l2 protein, mouse
• Quinolines
• Nucleotidyltransferases
• REV1 protein, human
• DNA-Directed DNA Polymerase
• Rev1 protein, mouse
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cisplatin (adverse effects, pharmacology, therapeutic use)
• DNA Damage (drug effects)
• DNA-Directed DNA Polymerase
• Female
• Gene Knockdown Techniques
• Humans
• Mad2 Proteins (metabolism)
• Mice
• Mice, Nude
• Mice, Transgenic
• Mutagenesis (drug effects)
• Neoplasms (drug therapy, metabolism, pathology)
• Nucleotidyltransferases (antagonists & inhibitors, chemistry, genetics, metabolism)
• Quinolines (chemistry, pharmacology, therapeutic use)
• Transfection
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays