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16.09.19 Discovery of first selective inhibitors of the Fanconi anaemia pathway that mediates chemotherapy resistance

last modified Nov 14, 2019 10:37 AM
Galanty and colleagues in the Jackson lab identify two small-molecule inhibitors of the Fanconi anemia pathway, necessary for cancer cells that are - or become - resistant to DNA cross-linking therapeutics. These provide leads for development of drugs to re-sensitise tumours to cross-linking agents such as cisplatin.

Small Molecule Inhibition of UBE2T/FANCL-mediated Ubiquitylation in the Fanconi Anemia Pathway

Corwall MJ et al. (2019) ACS Chemical Biology 14:2148-2154. DOI: 

10.1021/acschembio.9b00570.

 

Abstract from the paper

The Fanconi anemia pathway orchestrates the repair of DNA inter-strand crosslinks and stalled replication forks. A key step in this pathway is UBE2T and FANCL dependent monoubiquitylation of the FANCD2-FANCI complex.

The Fanconi anemia pathway represents an attractive therapeutic target because activation of this pathway has been linked to chemotherapy resistance in several cancers. However, very few selective inhibitors of ubiquitin conjugation pathways are known to date.

By using a high-throughput screen compatible assay, we have identified a small molecule inhibitor of UBE2T/FANCL-mediated FANCD2 monoubiquitylation that sensitizes cells to the DNA cross-linking agent, carboplatin.

Galanty Graphical Abstract linear

Graphical abstract from the paper

 

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Read more about research in the Jackson lab.

Watch Steve Jackson describe his research on YouTube.

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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Small Molecule Inhibition of UBE2T/FANCL-mediated Ubiquitylation in the Fanconi Anemia Pathway

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