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Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
TLDR
BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis, illustrating how different pathways cooperate to repair damage. Expand
Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM
TLDR
KU-55933 is a novel, specific, and potent inhibitor of the ATM kinase, which did not potentiate the cytotoxic effects of ionizing radiation on ataxia-telangiectasia cells, nor did it affect their cell cycle profile after DNA damage. Expand
High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs
TLDR
In vivo efficacy of AZD2281 against BRCA1-deficient breast cancer is demonstrated and how GEMMs of cancer can be used for preclinical evaluation of novel therapeutics and for testing ways to overcome or circumvent therapy resistance is illustrated. Expand
Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors.
TLDR
It is shown that tumor-specific genetic inactivation of P-glycoprotein increases the long-term response of BRCA1-deficient mouse mammary tumors to olaparib, but these tumors eventually developed PARPi resistance, which was minimized by long- term treatment with the novel PARP inhibitor AZD2461, which is a poor P- Glycoprotein substrate. Expand
4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1.
TLDR
A novel series of substituted 4-benzyl-2 H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 andPARP-2 are disclosed and shows standalone activity against BRCA1-deficient breast cancer cell lines. Expand
BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of poly (ADP-ribose) polymerase: An issue of potency
TLDR
It is shown that CAPAN-1 cells are in fact very sensitive to the potent PARP inhibitors KU0058684 (IC50 3.2nM) and K U0058948 (IC 50 3.4nM), and treatment with potent ParP inhibitors remains an exciting potential therapy for cancers involving BRCA1 or BRCa2 deficiency. Expand
Deubiquitylating enzymes and drug discovery: emerging opportunities
TLDR
This Review discusses issues and recent advances in understanding of DUB enzymology and biology as well as technological improvements that have contributed to the current interest in DUBs as therapeutic targets in diseases ranging from oncology to neurodegeneration. Expand
Selective Inhibition of BRCA2-Deficient Mammary Tumor Cell Growth by AZD2281 and Cisplatin
TLDR
The exquisite sensitivity of these cells to the PARP inhibitor AZD 2281, alone or in combination with cisplatin, provides strong support for AZD2281 as a novel targeted therapeutic against BRCA-deficient cancers. Expand
2,6-disubstituted pyran-4-one and thiopyran-4-one inhibitors of DNA-Dependent protein kinase (DNA-PK).
TLDR
Members of both structural classes were found to be selective inhibitors of DNA-PK over related phosphatidylinositol 3-kinase-related kinase (PIKK) family members. Expand
Chemosensitization of Cancer Cells by KU-0060648, a Dual Inhibitor of DNA-PK and PI-3K
TLDR
The proof-of-principle in vitro and in vivo chemosensitization with KU-0060648 justifies further evaluation of dual DNA-PK and PI-3K inhibitors. Expand
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