scholarly journals A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death

2021 ◽  
Author(s):  
Duncan E. Scott ◽  
Nicola J. Francis-Newton ◽  
May E. Marsh ◽  
Anthony G. Coyne ◽  
Gerhard Fischer ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

scholarly journals Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates Methotrexate anticancer effects

2020 ◽  
Author(s):  
Juan Miguel Baquero ◽  
Carlos Benítez-Buelga ◽  
Varshni Rajagopal ◽  
Zhao Zhenjun ◽  
Raúl Torres-Ruiz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Lines ◽  
Small Molecule ◽  
Oxidative Dna Damage ◽  
Genome Instability ◽  
Excision Repair ◽  
Small Molecule Inhibitor ◽  
Osteosarcoma Cell ◽  
Molecule Inhibitor

Abstract Background: The most common oxidative DNA lesion is 8-oxoguanine (8-oxoG) which is mainly recognized and excised by the glycosylase OGG1, initiating the Base Excision Repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress which disrupts telomere homeostasis triggering genome instability. Methods: We used U2OS OGG1-GFP osteosarcoma cell line to study the role of OGG1 at the telomeres in response to oxidative stress. Next, we investigated the effects of inactivating pharmacologically the BER during oxidative stress (OS) conditions by using a specific small molecule inhibitor of OGG1 (TH5487) in different human cell lines. Results: We have found that during OS, TH5487 effectively blocks BER initiation at telomeres causing accumulation of oxidized bases at this region, correlating with other phenotypes such as telomere losses, micronuclei formation and mild proliferation defects. Besides, the antimetabolite Methotrexate synergizes with TH5487 through induction of intracellular ROS formation, which potentiates TH5487 mediated telomere and genome instability in different cell lines. Conclusions: Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.

scholarly journals Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1

2008 ◽  
Vol 7 (8) ◽  
pp. 2394-2404 ◽  
Author(s):  
Alessandra Blasina ◽  
Jill Hallin ◽  
Enhong Chen ◽  
Maria Elena Arango ◽  
Eugenia Kraynov ◽  
...  
Keyword(s):  
Dna Damage ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Dna Damage Checkpoint ◽  
Checkpoint Kinase ◽  
Checkpoint Kinase 1 ◽  
Molecule Inhibitor

scholarly journals MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells

2015 ◽  
Vol 35 (6) ◽  
Author(s):  
Lijs Beke ◽  
Cenk Kig ◽  
Joannes T. M. Linders ◽  
Shannah Boens ◽  
An Boeckx ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Small Molecule ◽  
Damage Tolerance ◽  
Replication Stress ◽  
Small Molecule Inhibitor ◽  
Dna Damage Tolerance ◽  
Molecule Inhibitor ◽  
Senescence Phenotype

Protein kinase MELK has oncogenic properties and is highly overexpressed in some tumors. In the present study, we show that a novel MELK inhibitor causes both the inhibition and degradation of MELK, culminating in replication stress and a senescence phenotype.

scholarly journals A Small-Molecule Inhibitor of Bax and Bak Oligomerization Prevents Genotoxic Cell Death and Promotes Neuroprotection

2017 ◽  
Vol 24 (4) ◽  
pp. 493-506.e5 ◽  
Author(s):  
Xin Niu ◽  
Hetal Brahmbhatt ◽  
Philipp Mergenthaler ◽  
Zhi Zhang ◽  
Jing Sang ◽  
...  
Keyword(s):  
Cell Death ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

scholarly journals Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates Methotrexate anticancer effects

2020 ◽  
Author(s):  
Juan Miguel Baquero ◽  
Carlos Benítez-Buelga ◽  
Varshni Rajagopal ◽  
Zhao Zhenjun ◽  
Raúl Torres-Ruiz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Lines ◽  
Small Molecule ◽  
Oxidative Dna Damage ◽  
Genome Instability ◽  
Excision Repair ◽  
Small Molecule Inhibitor ◽  
Osteosarcoma Cell ◽  
Molecule Inhibitor

Abstract Background: The most common oxidative DNA lesion is 8-oxoguanine (8-oxoG) which is mainly recognized and excised by the glycosylase OGG1, initiating the Base Excision Repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress which disrupts telomere homeostasis triggering genome instability. Methods: We used U2OS OGG1-GFP osteosarcoma cell line to study the role of OGG1 at the telomeres in response to oxidative stress. Next, we investigated the effects of inactivating pharmacologically the BER during oxidative stress (OS) conditions by using a specific small molecule inhibitor of OGG1 (TH5487) in different human cell lines. Results: We have found that during OS, TH5487 effectively blocks BER initiation at telomeres causing accumulation of oxidized bases at this region, correlating with other phenotypes such as telomere losses, micronuclei formation and mild proliferation defects. Besides, the antimetabolite Methotrexate synergizes with TH5487 through induction of intracellular ROS formation, which potentiates TH5487 mediated telomere and genome instability in different cell lines. Conclusions: Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.

MLN4924, A Novel First in Class Small Molecule Inhibitor of the Nedd8 Activating Enzyme (NAE), Has Potent Activity in Preclinical Models of Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1021-1021
Author(s):  
Ronan T. Swords ◽  
Kevin R. Kelly ◽  
Peter G. Smith ◽  
James J. Gansey ◽  
Devalingam Mahalingam ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Small Molecule ◽  
Myeloid Leukemia ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Molecule Inhibitor ◽  
Acute Myeloid

Abstract Abstract 1021 Poster Board I-43 The coordinated balance between the synthesis and degradation of proteins is an important regulator of cancer cell biology. The ubiquitin-proteasome system (UPS) is responsible for the timed destruction of many proteins including key mediators of fundamental signaling cascades and critical regulators of cell cycle progression and transcription. Within the UPS, the E3 ligases are multi-protein complexes whose specificity is established by their individual components as well as post-translational modifications by various factors including the ubiquitin-like molecule, Nedd8. The Nedd8 activating enzyme (NAE) has been identified as an essential regulator of the Nedd8 conjugation pathway, which controls the activity of the cullin-dependent E3 ubiquitin ligases. The cullins direct the ubiquitination and subsequent degradation of many proteins with important roles in cell cycle progression (p27, cyclin E), DNA damage (Cdt-1), stress response (NRF-2, HIF1α) and signal transduction (IκBα). Acute myeloid leukemia (AML) is a disease of the elderly and prognosis is extremely poor with a median overall survival of just 2 months for untreated patients. As such, novel therapeutic strategies are urgently needed to improve clinical outcomes. Considering that Nedd8-mediated control of protein homeostasis is vitally important for the survival of AML cells, we hypothesized that disrupting this process would inhibit proliferation and induce cell death. We tested this hypothesis by investigating the preclinical anti-leukemic activity of MLN4924, a novel first in class small molecule inhibitor of the Nedd8 activating enzyme. MLN4924 induced DNA damage followed by rapid and selective caspase-dependent cell death in AML cell lines and primary AML cells from patients, but not in peripheral blood mononuclear cells from healthy donors. Transient exposure to MLN4924 impaired colony formation in a dose-dependent manner. Kinetic analysis of drug-induced effects on cell cycle distribution revealed that AML cells treated with MLN4924 initially arrested at the G1 transition prior to their subsequent accumulation in the sub-G1 compartment. Assays conducted using MV-411 cells with and without stable shRNA-mediated knockdown of FLT3 expression demonstrated that MLN4924 is highly effective independent of FLT3 status. Further investigation revealed that the activity of MLN4924 was preserved when cells were co-cultured with bone marrow stromal cells indicating that it has the ability to overcome the effects of stromal-mediated survival signaling that has been established to blunt the efficacy of relevant standard of care agents. MLN4924 induced a dose and time dependant increase in the expression of phospo-IκB, an important target for degradation through the Nedd8 conjugation pathway. The inhibitory effects of MLN4924 on NFκB were confirmed by demonstrating that the transcriptional activity of the NFκB p65 subunit was significantly reduced following drug exposure. Moreover, treatment of immunodeficient mice implanted with HL-60 human leukemia cells with MLN4924 led to an inhibition of neddylated cullins, accumulation of phospho-IκBα and achieved complete and stable disease regression. Our results indicate that MLN4924 is a highly promising novel agent for the treatment of AML and warrants further evaluation in clinical trials. Disclosures: Smith: Millennium Pharmaceuticals: Employment. Gansey:Millennium Pharmaceuticals: Employment.

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