Skip to main content
Journal cover image

A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy.

Publication ,  Journal Article
Wojtaszek, JL; Chatterjee, N; Najeeb, J; Ramos, A; Lee, M; Bian, K; Xue, JY; Fenton, BA; Park, H; Li, D; Hemann, MT; Hong, J; Walker, GC; Zhou, P
Published in: Cell
June 27, 2019

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Cell

DOI

EISSN

1097-4172

Publication Date

June 27, 2019

Volume

178

Issue

1

Start / End Page

152 / 159.e11

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Burden
  • Transfection
  • Quinolines
  • Nucleotidyltransferases
  • Neoplasms
  • Mutagenesis
  • Mice, Transgenic
  • Mice, Nude
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wojtaszek, J. L., Chatterjee, N., Najeeb, J., Ramos, A., Lee, M., Bian, K., … Zhou, P. (2019). A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy. Cell, 178(1), 152-159.e11. https://doi.org/10.1016/j.cell.2019.05.028
Wojtaszek, Jessica L., Nimrat Chatterjee, Javaria Najeeb, Azucena Ramos, Minhee Lee, Ke Bian, Jenny Y. Xue, et al. “A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy.Cell 178, no. 1 (June 27, 2019): 152-159.e11. https://doi.org/10.1016/j.cell.2019.05.028.
Wojtaszek JL, Chatterjee N, Najeeb J, Ramos A, Lee M, Bian K, et al. A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy. Cell. 2019 Jun 27;178(1):152-159.e11.
Wojtaszek, Jessica L., et al. “A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy.Cell, vol. 178, no. 1, June 2019, pp. 152-159.e11. Pubmed, doi:10.1016/j.cell.2019.05.028.
Wojtaszek JL, Chatterjee N, Najeeb J, Ramos A, Lee M, Bian K, Xue JY, Fenton BA, Park H, Li D, Hemann MT, Hong J, Walker GC, Zhou P. A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy. Cell. 2019 Jun 27;178(1):152-159.e11.
Journal cover image

Published In

Cell

DOI

EISSN

1097-4172

Publication Date

June 27, 2019

Volume

178

Issue

1

Start / End Page

152 / 159.e11

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Burden
  • Transfection
  • Quinolines
  • Nucleotidyltransferases
  • Neoplasms
  • Mutagenesis
  • Mice, Transgenic
  • Mice, Nude
  • Mice