scholarly journals Coupling Metastasis to pH-Sensing GPR68 Using a Novel Small Molecule Inhibitor

2019 ◽  
Author(s):  
Charles H. Williams ◽  
Leif R. Neitzel ◽  
Pratap Karki ◽  
Brittany D. Keyser ◽  
Timothy E. Thayer ◽  
...  
Keyword(s):  
Neural Crest ◽  
Cancer Progression ◽  
Small Molecule ◽  
Cancer Metastasis ◽  
Association Studies ◽  
Small Molecule Inhibitor ◽  
Migration And Invasion ◽  
Ph Sensing ◽  
Molecule Inhibitor

AbstractAn acidic milieu is a hallmark of the glycolytic metabolism that occurs in cancerous cells. The acidic environment is known to promote cancer progression, but the underlying signaling and cell biological underpinnings of these phenomena are not well understood. Here, we describe ogremorphin, a first-in-class small-molecule inhibitor of GPR68, an extracellular proton-sensing and mechanosensing G protein–coupled receptor. Ogremorphin was discovered in a chemical genetic zebrafish screen for its ability to perturb neural crest development, which shares basic cell behaviors of migration and invasion with cancer metastasis. Ogremorphin also inhibited migration and invasive behavior of neural crest–derived human melanoma cells in vitro. Furthermore, in phenome-wide association studies (PheWAS), we identified an aberrantly activated variant of GPR68, which is associated with cancer metastasis in vivo and promotes invasive phenotypes of cancer cells in vitro. Thus, extracellular proton-sensing GPR68 signaling promotes cell migration and invasion during embryonic development and may do likewise in cancer progression.

scholarly journals Development of Oxadiazole-Based ODZ10117 as a Small-Molecule Inhibitor of STAT3 for Targeted Cancer Therapy

2019 ◽  
Vol 8 (11) ◽  
pp. 1847 ◽  
Author(s):  
Kim ◽  
Lee ◽  
Song ◽  
Park ◽  
Gadhe ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Small Molecule ◽  
Nuclear Translocation ◽  
Small Molecule Inhibitor ◽  
Sh2 Domain ◽  
Migration And Invasion ◽  
Targeted Cancer Therapy ◽  
In Vivo Models ◽  
Molecule Inhibitor

Persistently activated STAT3 is a promising target for a new class of anticancer drug development and cancer therapy, as it is associated with tumor initiation, progression, malignancy, drug resistance, cancer stem cell properties, and recurrence. Here, we discovered 3-(2,4-dichloro-phenoxymethyl)-5-trichloromethyl-[1,2,4]oxadiazole (ODZ10117) as a small-molecule inhibitor of STAT3 to be used in STAT3-targeted cancer therapy. ODZ10117 targeted the SH2 domain of STAT3 regardless of other STAT family proteins and upstream regulators of STAT3, leading to inhibition of the tyrosine phosphorylation, dimerization, nuclear translocation, and transcriptional activity of STAT3. The inhibitory effect of ODZ10117 on STAT3 was stronger than the known STAT3 inhibitors such as S3I-201, STA-21, and nifuroxazide. ODZ10117 suppressed the migration and invasion, induced apoptosis, reduced tumor growth and lung metastasis, and extended the survival rate in both in vitro and in vivo models of breast cancer. Overall, we demonstrated that ODZ10117 is a novel STAT3 inhibitor and may be a promising agent for the development of anticancer drugs.

scholarly journals Inhibiting receptor tyrosine kinase AXL with small molecule inhibitor BMS-777607 reduces glioblastoma growth, migration, and invasion in vitro and in vivo

Oncotarget ◽  
2016 ◽  
Vol 7 (9) ◽  
pp. 9876-9889 ◽  
Author(s):  
Julia Onken ◽  
Robert Torka ◽  
Sören Korsing ◽  
Josefine Radke ◽  
Irina Krementeskaia ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Small Molecule ◽  
Receptor Tyrosine Kinase ◽  
Small Molecule Inhibitor ◽  
Migration And Invasion ◽  
Molecule Inhibitor

scholarly journals A Novel Small-Molecule Inhibitor of Protein Kinase D Blocks Pancreatic Cancer Growth In vitro and In vivo

2010 ◽  
Vol 9 (5) ◽  
pp. 1136-1146 ◽  
Author(s):  
Kuzhuvelil B. Harikumar ◽  
Ajaikumar B. Kunnumakkara ◽  
Nobuo Ochi ◽  
Zhimin Tong ◽  
Amit Deorukhkar ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Protein Kinase ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Cancer Growth ◽  
Protein Kinase D ◽  
Molecule Inhibitor

scholarly journals lncRNA NORAD Contributes to Colorectal Cancer Progression by Inhibition of miR-202-5p

2018 ◽  
Vol 26 (9) ◽  
pp. 1411-1418 ◽  
Author(s):  
Jie Zhang ◽  
Xiao-Yan Li ◽  
Ping Hu ◽  
Yuan-Sheng Ding
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Cancer Metastasis ◽  
Cellular Proliferation ◽  
Inhibitory Effect ◽  
Migration And Invasion ◽  
Competing Endogenous Rna

Previous study indicates that long noncoding RNA NORAD could serve as a competing endogenous RNA to pancreatic cancer metastasis. However, its role in colorectal cancer (CRC) needs to be investigated. In the present study, we found that the expression of NORAD was significantly upregulated in CRC tissues. Furthermore, the expression of NORAD was positively related with CRC metastasis and patients’ poor prognosis. Knockdown of NORAD markedly inhibited CRC cell proliferation, migration, and invasion but induced cell apoptosis in vitro. In vivo experiments also indicated an inhibitory effect of NORAD on tumor growth. Mechanistically, we found that NORAD served as a competing endogenous RNA for miR-202-5p. We found that there was an inverse relationship between the expression of NORAD and miR-202-5p in CRC tissues. Moreover, overexpression of miR-202-5p in SW480 and HCT116 cells significantly inhibited cellular proliferation, migration, and invasion. Taken together, our study demonstrated that the NORAD/miR-202-5p axis plays a pivotal function on CRC progression.

scholarly journals Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB–VCAM-1 axis

2020 ◽  
Vol 6 (31) ◽  
pp. eaaz7815
Author(s):  
Yue Li ◽  
Ahmad M. N. Alhendi ◽  
Mei-Chun Yeh ◽  
Mina Elahy ◽  
Fernando S. Santiago ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Small Molecule ◽  
Wound Repair ◽  
Network Formation ◽  
Small Molecule Inhibitor ◽  
Age Related Macular Degeneration ◽  
Endothelial Cell Proliferation ◽  
Age Related ◽  
Molecule Inhibitor

Vascular permeability and angiogenesis underpin neovascular age-related macular degeneration and diabetic retinopathy. While anti-VEGF therapies are widely used clinically, many patients do not respond optimally, or at all, and small-molecule therapies are lacking. Here, we identified a dibenzoxazepinone BT2 that inhibits endothelial cell proliferation, migration, wound repair in vitro, network formation, and angiogenesis in mice bearing Matrigel plugs. BT2 interacts with MEK1 and inhibits ERK phosphorylation and the expression of FosB/ΔFosB, VCAM-1, and many genes involved in proliferation, migration, angiogenesis, and inflammation. BT2 reduced retinal vascular leakage following rat choroidal laser trauma and rabbit intravitreal VEGF-A165 administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A165 expression. BT2 reduced retinal leakage in rats at least as effectively as aflibercept, a first-line therapy for nAMD/DR. BT2 withstands boiling or autoclaving and several months’ storage at 22°C. BT2 is a new small-molecule inhibitor of vascular permeability and angiogenesis.

A Novel Small Molecule Inhibitor for Aurora-A Kinase Inhibits the Growth of Cervical Cancer In Vitro and In Vivo.

2010 ◽  
Vol 83 (Suppl_1) ◽  
pp. 344-344
Author(s):  
Patricia Y. Akinfenwa ◽  
Nonna V. Kolomeyevskaya ◽  
Claire M. Mach ◽  
Zhen Li ◽  
Matthew L. Anderson
Keyword(s):  
Cervical Cancer ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Molecule Inhibitor
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