scholarly journals Virtual Screening for DNA Repair Inhibitors

10.5772/24436 ◽  
2011 ◽  
Author(s):  
Barakat ◽  
K. ◽  
Tuszynski J.
Keyword(s):  
Dna Repair ◽  
Virtual Screening ◽  
Dna Repair Inhibitors

Search for DNA Repair Inhibitors:  Selective Binding of Nucleic Bases−Acridine Conjugates to a DNA Duplex Containing an Abasic Site†

1997 ◽  
Vol 40 (21) ◽  
pp. 3346-3352 ◽  
Author(s):  
Nathalie Berthet ◽  
Jean-François Constant ◽  
Martine Demeunynck ◽  
Pierre Michon ◽  
Jean Lhomme
Keyword(s):  
Dna Repair ◽  
Abasic Site ◽  
Dna Duplex ◽  
Selective Binding ◽  
Nucleic Bases ◽  
Dna Repair Inhibitors

285 The “Dbait”: a New Class of DNA Repair Inhibitors That Sensitize Tumors to Treatment

2012 ◽  
Vol 48 ◽  
pp. 87-88
Author(s):  
M. Dutreix ◽  
A. Croset ◽  
M. Quanz ◽  
J.S. Sun
Keyword(s):  
Dna Repair ◽  
New Class ◽  
Dna Repair Inhibitors

scholarly journals RDNA-06. TARGETING IDH1/2-MUTANT GLIOMAS WITH UNIQUE COMBINATIONS OF DNA REPAIR INHIBITORS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi208-vi208
Author(s):  
Amrita Sule ◽  
Ranjit Bindra
Keyword(s):  
Clinical Trials ◽  
Dna Repair ◽  
Myeloid Leukemia ◽  
Parp Inhibitors ◽  
Low Grade ◽  
High Fidelity ◽  
Isocitrate Dehydrogenase 1 ◽  
Dna Repair Inhibitors ◽  
Mutant Idh1 ◽  
Tumor Types

Abstract Mutations in the Isocitrate Dehydrogenase-1 and -2 (IDH1/2) genes occur in the vast majority of low-grade and secondary high-grade gliomas. These neomorphic mutations occur early on in gliomagenesis leading to the production of 2-Hydroxyglutarate (2HG). 2HG has been implicated in tumorigenesis via inhibiting α-ketoglutarate (αKG)-dependent dioxygenases. Our group recently demonstrated that the production of 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state of “BRCAness”. We initially found that mutant IDH1/2-induced BRCAness confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, a finding which now has been replicated by multiple independent laboratories. Although IDH1/2 mutations were first identified in gliomas and acute myeloid leukemia (AML) cells, multiple other tumor types have subsequently been shown to harbor these mutations. Current clinical trials are testing the efficacy of PARP inhibitors as a monotherapy, as well as in combination with other DNA repair inhibitors. Here, we demonstrate that novel combinations of DNA repair inhibitors can be utilized to synergistically target IDH1/2-mutant glioma cells. In particular, we demonstrate potent synergy with ATRi and PARPis, a finding which was validated in multiple structurally unique drugs within these classes. As this combination is active in BRCA1/2-mutant cancers, in particular after the emergence of PARPi resistance, these data suggest are consistent with an underlying HR defect in IDH1/2-mutant gliomas. These preclinical investigations will provide a blueprint for future clinical trials combining PARP and ATR inhibitors in the treatment of glioblastoma.

Sign in / Sign up

Export Citation Format

Share Document