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Protein‐protein interaction inhibitors of the Fanconi anemia DNA repair pathway
Author(s) -
Voter Andrew F.,
Manthei Kelly A.,
Keck James L.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.577.1
Subject(s) - fanconi anemia , isothermal titration calorimetry , dna , chemistry , dna repair , small molecule , in vivo , genome instability , computational biology , microbiology and biotechnology , biochemistry , biophysics , cancer research , dna damage , genetics , biology
Upregulation of the Fanconi anemia DNA repair pathway is a frequent mechanism by which tumors evolve resistance to DNA crosslinking chemotherapies. Previous studies have determined that the interaction between FANCM and the RecQ mediated genome instability (RMI) complex is essential for crosslink repair in this pathway and that disruption of the interface causes sensitization to DNA crosslinking agents. To identify small molecules that disrupt this interaction, we developed a high‐throughput fluorescence polarization assay that was used to screen a library of 75,000 small molecules. We confirmed the activity of a selective inhibitor in an orthogonal proximity assay and detected its direct physical interaction with the RMI complex using surface plasmon resonance and isothermal titration calorimetry. More potent inhibitors have been identified by structure activity relationship studies. These potent small molecules will be tested for synergies with DNA crosslinking agents in vivo to assess for therapeutic potential. Support or Funding Information University of Wisconsin – Madison Medical Scientist Training Program (T32GM008692), Integrated Program in Biochemistry, ICTR Clinical and Translational Science award (UL1TR00427) and traineeship (TL1TR000429) and the NCI (R21CA178475‐01)