scholarly journals Small Molecule Inhibitor of Type Three Secretion System Belonging to a Class 2,4-disubstituted-4H-[1,3,4]-thiadiazine-5-ones Improves Survival and Decreases Bacterial Loads in an AirwayPseudomonas aeruginosaInfection in Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Anna B. Sheremet ◽  
Naylia A. Zigangirova ◽  
Egor S. Zayakin ◽  
Sergei I. Luyksaar ◽  
Lydia N. Kapotina ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Secretion System ◽  
Resistant Bacteria ◽  
Lung Pathology ◽  
Antibiotic Resistant ◽  
Molecule Inhibitor ◽  
Type Three Secretion System ◽  
Type Three Secretion

Pseudomonas aeruginosais a cause of high mortality in burn, immunocompromised, and surgery patients. High incidence of antibiotic resistance in this pathogen makes the existent therapy inefficient. Type three secretion system (T3SS) is a leading virulence system ofP. aeruginosathat actively suppresses host resistance and enhances the severity of infection. Innovative therapeutic strategies aiming at inhibition of type three secretion system ofP. aeruginosaare highly attractive, as they may reduce the severity of clinical manifestations and improve antibacterial immune responses. They may also represent an attractive therapy for antibiotic-resistant bacteria. Recently our laboratory developed a new small molecule inhibitor belonging to a class 2,4-disubstituted-4H-[1,3,4]-thiadiazine-5-ones, Fluorothiazinon (FT), that effectively suppressed T3SS in chlamydia and salmonellain vitroandin vivo.In this study, we evaluate the activity of FT towards antibiotic-resistant clinical isolates ofP. aeruginosaexpressing T3SS effectors ExoU and ExoS in an airway infection model. We found that FT reduced mortality and bacterial loads and decrease lung pathology and systemic inflammation. In addition, we show that FT inhibits the secretion of ExoT and ExoY, reduced bacteria cytotoxicity, and increased bacteria internalizationin vitro. Overall, FT shows a strong potential as an antibacterial therapy of antibiotic-resistantP. aeruginosainfection.

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 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

scholarly journals Small molecule inhibitor of HSP47 prevents pro-fibrotic mechanisms of fibroblasts in vitro

2020 ◽  
Vol 530 (3) ◽  
pp. 561-565
Author(s):  
Takuto Miyamura ◽  
Noriho Sakamoto ◽  
Tomoyuki Kakugawa ◽  
Hirokazu Taniguchi ◽  
Yoshiko Akiyama ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

scholarly journals A Small Molecule Inhibitor of the β-Catenin-TCF4 Interaction Suppresses Colorectal Cancer Growth In Vitro and In Vivo

EBioMedicine ◽  
2017 ◽  
Vol 25 ◽  
pp. 22-31 ◽  
Author(s):  
Seung Ho Shin ◽  
Do Young Lim ◽  
Kanamata Reddy ◽  
Margarita Malakhova ◽  
Fangfang Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Cancer Growth ◽  
Molecule Inhibitor

QLT0267, a Small Molecule Inhibitor of ILK and FLT3 Is Cytotoxic to Acute Myeloid Leukemia (AML) ‘Stem Cells’ Detected in Immunodeficient Mice.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 950-950
Author(s):  
Andrew L Muranyi ◽  
Shoukat Dedhar ◽  
Donna E. Hogge
Keyword(s):  
Stem Cells ◽  
Small Molecule ◽  
Cell Cycle Progression ◽  
Small Molecule Inhibitor ◽  
Mouse Bone Marrow ◽  
Immunodeficient Mice ◽  
Akt Phosphorylation ◽  
Molecule Inhibitor ◽  
Integrin Linked Kinase

Abstract The phosphatidylinositol-3-kinase (PI-3K) and FMS-like tyrosine kinase 3 (FLT3) receptor signaling pathways are constitutively active in many AML blast samples suggesting these as therapeutic targets. Integrin linked kinase (ILK) is involved in Akt and GSK3 activation, key downstream effectors of the PI-3K pathway, and participates in the regulation of apoptosis, cell cycle progression, and tumour angiogenesis in many solid tumours. ILK is also expressed ubiquitously in AML blasts. In previous experiments to explore the effect of targeting ILK in AML, QLT0267, a small molecule inhibitor of ILK, was shown to be cytotoxic to AML blasts and colony forming cells (CFC) from some patient samples. Since AML samples containing the FLT3 internal-tandem duplication (ITD) were more susceptible to QLT0267-induced cell kill than FLT3 wildtype (WT) cells we tested the possibility that QLT0267 could inhibit FLT3 as well as ILK. In vitro kinase assays from 4 AML samples showed that QLT0267 produces equivalent inhibition of ILK and FLT3 (both WT and ITD) while Western blotting of 2 AML samples cultured with QLT0267 showed a dose and time dependant decrease in both FLT3 and Akt phosphorylation. 5 AML samples (4 FLT3-ITD, 1 FLT3 WT), were cultured for 24 h ± QLT0267, and assayed for AML CFC or 6-week suspension culture initiating cells (SC-IC). The mean percents kill for 20 and 50 μM QLT0267, respectively, were 92%, and 100% for AML-CFC and 71% and 92% for SC-IC. CD34+CD38− blasts (enriched for AML cells which engraft in immunodeficient mice) from these same samples were analyzed for expression of ILK, pGSK3, and FLT3. Intracellular staining detected ILK and pGSK3 protein in CD34+CD38− cells at levels similar to those present in other AML cell populations. QRT-PCR showed FLT-3 expression in CD34+CD38− cells from all 5 AML samples with 2 of these showing higher expression in this population than in the remainder of AML blasts. To determine if simultaneous targeting of ILK and FLT3 would kill AML progenitors that engraft in mice 4 AML samples (FLT3-ITD +) were cultured for 24 h ± QLT0267, and then injected IV into sublethally irradiated NOD/SCID or NOD/SCID IL2γRnull mice. As shown in the Table, treatment with 20 μM QLT0267 significantly reduced AML engraftment for 3 of 4 samples while the 50 μM dose was effective for 2 of the 3 samples tested (p<0.05, student t-test). Thus, combined targeting of ILK and FLT3 will kill AML cells, including candidate leukemic stem cells that sustain long-term engraftment in mice. Further preclinical evaluation of the potential therapeutic usefulness of this strategy is ongoing. QLT0267 (μM) 0 20 50 AML Sample % engraftment ± SD AML cells in mouse bone marrow
 Week 16 (n=) 1 86 ± 11
 (4) 53 ± 30
 (6) 2 ± 3
 (4) 2 46 ± 45
 (5) 3 ± 5
 (6) 0
 (2) 3 47 ± 40
 (5) 1 ± 2
 (4) 0
 (6) 4 90 ± 14
 (3) 1 ± 1
 (3) ND

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