Abstract 3719: TAK-243, a small molecule inhibitor of the ubiquitin activating enzyme (UAE), disrupts DNA damage repair and sensitizes tumor cells and xenografts to ionizing radiation

2016 ◽  
Author(s):  
Michael A. Milhollen ◽  
Judy Qiuju Shi ◽  
Tary Traore ◽  
Jessica Huck ◽  
Darshan Sappal ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Tumor Cells ◽  
Small Molecule ◽  
Dna Damage Repair ◽  
Small Molecule Inhibitor ◽  
Damage Repair ◽  
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 Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

2019 ◽  
Vol 20 (19) ◽  
pp. 4728 ◽  
Author(s):  
Hwani Ryu ◽  
Hyun-Kyung Choi ◽  
Hyo Jeong Kim ◽  
Ah-Young Kim ◽  
Jie-Young Song ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Tyrosine Kinase ◽  
Small Molecule ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Class Iii ◽  
Damage Repair ◽  
Repair Genes

Class III receptor tyrosine kinase (RTK) inhibitors targeting mainly FLT3 or c-KIT have not been well studied in lung cancer. To identify a small molecule potentially targeting class III RTK, we synthesized novel small molecule compounds and identified 5-(4-bromophenyl)-N-(naphthalen-1-yl) oxazol-2-amine (AIU2001) as a novel class III RKT inhibitor. In an in vitro kinase profiling assay, AIU2001 inhibited the activities of FLT3, mutated FLT3, FLT4, and c-KIT of class III RTK, and the proliferation of NSCLC cells in vitro and in vivo. AIU2001 induced DNA damage, reactive oxygen species (ROS) generation, and cell cycle arrest in the G2/M phase. Furthermore, AIU2001 suppressed the DNA damage repair genes, resulting in the ‘BRCAness’/‘DNA-PKness’ phenotype. The mRNA expression level of STAT5 was downregulated by AIU2001 treatment and knockdown of STAT5 inhibited the DNA repair genes. Our results show that compared to either drug alone, the combination of AIU2001 with a poly (ADP-ribose) polymerase (PARP) inhibitor olaparib or irradiation showed synergistic efficacy in H1299 and A549 cells. Hence, our findings demonstrate that AIU2001 is a candidate therapeutic agent for NSCLC and combination therapies with AIU2001 and a PARP inhibitor or radiotherapy may be used to increase the therapeutic efficacy of AIU2001 due to inhibition of DNA damage repair.

Analysis of ionizing radiation-induced foci of DNA damage repair proteins

2005 ◽  
Vol 574 (1-2) ◽  
pp. 22-33 ◽  
Author(s):  
Lieneke R. van Veelen ◽  
Tiziana Cervelli ◽  
Mandy W.M.M. van de Rakt ◽  
Arjan F. Theil ◽  
Jeroen Essers ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Dna Damage Repair ◽  
Damage Repair ◽  
Radiation Induced

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.

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