Discovery of DNA repair inhibitors by combinatorial library profiling.

Abstract:

:Small molecule inhibitors of DNA repair are emerging as potent and selective anticancer therapies, but the sheer magnitude of the protein networks involved in DNA repair processes poses obstacles to discovery of effective candidate drugs. To address this challenge, we used a subtractive combinatorial selection approach to identify a panel of peptide ligands that bind DNA repair complexes. Supporting the concept that these ligands have therapeutic potential, we show that one selected peptide specifically binds and noncompetitively inactivates DNA-PKcs, a protein kinase critical in double-strand DNA break repair. In doing so, this ligand sensitizes BRCA-deficient tumor cells to genotoxic therapy. Our findings establish a platform for large-scale parallel screening for ligand-directed DNA repair inhibitors, with immediate applicability to cancer therapy.

journal_name

Cancer Res

journal_title

Cancer research

authors

Moeller BJ,Sidman RL,Pasqualini R,Arap W

doi

10.1158/0008-5472.CAN-10-2361

subject

Has Abstract

pub_date

2011-03-01 00:00:00

pages

1816-24

issue

5

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-10-2361

journal_volume

71

pub_type

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