scholarly journals INOS Dimerization Inhibitor ASP9853

2020 ◽  
Author(s):  
Keyword(s):  
Dimerization Inhibitor

Development of an HPLC-UV Method for Quantification of Stattic

2019 ◽  
Vol 15 (6) ◽  
pp. 568-573
Author(s):  
Soheil Sedaghat ◽  
Ommoleila Molavi ◽  
Akram Faridi ◽  
Ali Shayanfar ◽  
Mohammad Reza Rashidi
Keyword(s):  
High Performance ◽  
Accurate Method ◽  
Plasma Samples ◽  
Promising Target ◽  
Relative Standard ◽  
Dimerization Inhibitor ◽  
Oncogenic Protein ◽  
First Time ◽  
Transcription 3

Background: Signal transducer and activator of transcription 3 (STAT3), an oncogenic protein found constitutively active in many types of human malignancies, is considered to be a promising target for cancer therapy. Objective: In this study for the first time, a simple and accurate method has been developed for the determination of a STAT3 dimerization inhibitor called stattic in aqueous and plasma samples. Methods: A reverse-phase high-performance liquid chromatography (RP-HPLC) composed of C18 column as stationary phase, and the mixture of acetonitrile (60%) and water (40%) as mobile phase with a UV detection at 215 nm were applied for quantification of stattic. The developed method was validated by Food and Drug Administration (FDA) guideline. Results: The method provided a linear range between 1-40 and 2.5-40 µg mL-1 for aqueous and plasma samples, respectively, with a correlation coefficient of 0.999. The accuracy (as recovery) of the developed method was found to be between 95-105% for aqueous medium and 85-115% for plasma samples. The precision (as relative standard deviation) for aqueous and plasma samples was less than 6% and 15%, respectively. The sensitivity of the developed method based on FDA guideline was 1 µg mL-1 for aqueous and 2.5 µg mL-1 for plasma samples. Conclusion: These results show that the established method is a fast and accurate quantification for stattic in aqueous and plasma samples.

scholarly journals Identification of a natural product-like STAT3 dimerization inhibitor by structure-based virtual screening

2014 ◽  
Vol 5 (6) ◽  
pp. e1293-e1293 ◽  
Author(s):  
L-J Liu ◽  
K-H Leung ◽  
D S-H Chan ◽  
Y-T Wang ◽  
D-L Ma ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Natural Product ◽  
Dimerization Inhibitor

Identification of predictive markers of clinical activity from a phase II trial of single agent pertuzumab (rhuMab 2C4), a HER dimerization inhibitor, in advanced ovarian cancer (OC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3001-3001 ◽  
Author(s):  
L. Amler ◽  
M. S. Gordon ◽  
A. Strauss ◽  
N. Rabbee ◽  
M. K. Derynck ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Advanced Ovarian Cancer ◽  
Ca 125 ◽  
Clinical Activity ◽  
Fresh Tissue ◽  
Formalin Fixed Paraffin ◽  
Heavily Pretreated ◽  
Dimerization Inhibitor

3001 Background: Pertuzumab (P), a humanized HER2 antibody, represents a new class of targeted agents called HER dimerization inhibitors (HDIs). P inhibits dimerization of HER2 with EGFR, HER3 and HER4, and subsequently inhibits signaling through MAP and PI3 kinases. Interim data from a phase II trial suggested that P has activity in OC, especially in a subset of tumors with activated HER2 (Abstract #5051 ASCO 2005). Methods: 123 pts with relapsed OC were treated with P. Cohort 1 was treated with 840mg followed by 420mg and cohort 2 with 1050mg every 3 weeks. Fresh tissue biopsies were mandated from Cohort 1, and archival formalin fixed paraffin tissue (FFPET ) were obtained from both cohorts. Molecular expression studies from FFPET and fresh tissue were conducted. Results: From final data of 117 evaluable pts, 5 pts had objective partial responses (RR = 4.3%). Eight pts (6.8%) had SD for ≥ 6 months, and an additional 4 pts (3.4%) had SD with CA-125 reduction of ≥50%. Overall rate of activity = 14.5%. Of the 65 fresh tumor biopsies, 28 were evaluable and 8 (28.6%) were positive for phosphorylated HER2 (pHER2) by ELISA. Among pts who had pHER2 status determined, TTP was 20.9 weeks for pHER2+ pts (n=8), compared to 5.8 weeks for pHER2- (n = 20). Data from microarray expression profiling were analyzed with respect to pHER2 status from the same tumors. The expression levels of HER2, EGFR and HER3 in combination with the expression of certain HER ligands may be predictive of pHER2 status. We have extended these analyses to qRT-PCR from macrodissected FFPET of HER receptors and ligands. This was analyzed with respect to clinical outcome. Preliminary analyses of expression data suggest that HER receptors and ligands may be promising candidates for diagnostic markers. Updated data in 78 OC pts will be presented. Conclusions: Clinical activity was observed in 14.5% of pts with heavily pretreated OC (PRs, SD ≥ 6 months, and SD with CA-125 reductions of ≥50%). This study suggests that P may be active in OC, and that specific HER receptors and ligands may be promising diagnostics for identifying tumors responsive to P. [Table: see text]

Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab

2005 ◽  
Vol 55 (6) ◽  
pp. 717-727 ◽  
Author(s):  
Camellia W. Adams ◽  
David E. Allison ◽  
Kelly Flagella ◽  
Leonard Presta ◽  
Janet Clarke ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Recombinant Monoclonal Antibody ◽  
Dimerization Inhibitor

Inducible Nitric Oxide Synthase Dimerization Inhibitor Prevents Endotoxin-Induced Hemodynamic Changes in Mice

2002 ◽  
Vol 96 (Sup 2) ◽  
pp. A429
Author(s):  
Fumito Ichinose ◽  
Ryuji Hataishi ◽  
Noriko Kawai ◽  
John F. Parkinson ◽  
Warren M. Zapol
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Hemodynamic Changes ◽  
Dimerization Inhibitor ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

A selective inducible NOS dimerization inhibitor prevents systemic, cardiac, and pulmonary hemodynamic dysfunction in endotoxemic mice

2003 ◽  
Vol 285 (6) ◽  
pp. H2524-H2530 ◽  
Author(s):  
Fumito Ichinose ◽  
Ryuji Hataishi ◽  
Justina C. Wu ◽  
Noriko Kawai ◽  
Ana Clara Tude Rodrigues ◽  
...  
Keyword(s):  
Myocardial Dysfunction ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Selective Inhibition ◽  
Systemic Blood Pressure ◽  
No Production ◽  
Endotoxin Challenge ◽  
Systemic Hypotension ◽  
Pulmonary Hemodynamic ◽  
Dimerization Inhibitor ◽  
Nos Isoforms

Increased nitric oxide (NO) production by inducible NO synthase (NOS2), an obligate homodimer, is implicated in the cardiovascular sequelae of sepsis. We tested the ability of a highly selective NOS2 dimerization inhibitor (BBS-2) to prevent endotoxin-induced systemic hypotension, myocardial dysfunction, and impaired hypoxic pulmonary vasoconstriction (HPV) in mice. Mice were challenged with Escherichia coli endotoxin before treatment with BBS-2 or vehicle. Systemic blood pressure was measured before and 4 and 7 h after endotoxin challenge, and echocardiographic parameters of myocardial function were measured before and 7 h after endotoxin challenge. The pulmonary vasoconstrictor response to left mainstem bronchus occlusion, which is a measure of HPV, was studied 22 h after endotoxin challenge. BBS-2 treatment alone did not alter baseline hemodynamics. BBS-2 treatment blocked NOS2 dimerization and completely inhibited the endotoxin-induced increase of plasma nitrate and nitrite levels. Treatment with BBS-2 after endotoxin administration prevented systemic hypotension and attenuated myocardial dysfunction. BBS-2 also prevented endotoxin-induced impairment of HPV. In contrast, treatment with NG-nitro-l-arginine methyl ester, which is an inhibitor of all three NOS isoforms, prevented the systemic hypotension but further aggravated the myocardial dysfunction associated with endotoxin challenge. Treatment with BBS-2 prevented endotoxin from causing key features of cardiovascular dysfunction in endotoxemic mice. Selective inhibition of NOS2 dimerization with BBS-2, while sparing the activities of other NOS isoforms, may prove to be a useful treatment strategy in sepsis.

Inducible nitric oxide synthase dimerization inhibitor prevents cardiovascular and renal morbidity in sheep with combined burn and smoke inhalation injury

2003 ◽  
Vol 285 (6) ◽  
pp. H2430-H2436 ◽  
Author(s):  
Perenlei Enkhbaatar ◽  
Kazunori Murakami ◽  
Katsumi Shimoda ◽  
Akio Mizutani ◽  
Lillian Traber ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Inducible Nitric Oxide Synthase ◽  
Sham Group ◽  
Left Ventricular ◽  
Smoke Inhalation ◽  
Volume Index ◽  
Dimerization Inhibitor ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Inducible nitric oxide synthase (iNOS) is implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). ARDS treatment is frequently complicated by significant extrapulmonary comorbidity. This study was designed to clarify the role of iNOS in mediating extrapulmonary comorbidity in sheep after combined burn and smoke inhalation injuries using a potent and highly selective iNOS dimerization inhibitor, BBS-2. Twenty-two female sheep were operatively prepared. After 5 days of recovery, tracheostomy was performed under ketamine-halothane anesthesia. Sheep were given a 40% total body surface third-degree burns and insufflated with cotton smoke (48 breaths, <40°C). Sheep were divided into four groups: noninjured and nontreated (sham group; n = 6), noninjured but treated with BBS-2 (sham/BBS-2 group; n = 4), injured but nontreated (control group, n = 6), and injured but treated with 100 μg · kg–1 · h–1 BBS-2 (BBS-2 group; n = 6). Evaluation was in a laboratory intensive care unit setting for 48 h. The sham group had stable cardiopulmonary and systemic hemodynamics. Control animals showed multiple signs of morbidity. Decreased left ventricular stroke work index and stroke volume index with elevated left atrial pressure indicated myocardial depression. Systemic vascular leak was evidenced by robust hemoconcentration, decreased plasma oncotic pressure, and increased transvascular fluid flux into the lymphatic system. Finally, severely impaired renal function (urinary output) was associated with adverse net fluid balance. Treatment with BBS-2 prevented all these morbidities without adversely effecting cardiovascular hemodynamics such as cardiac index and mean arterial pressure. The results identify a major role for iNOS in mediating extrapulmonary comorbidity in a clinically relevant and severe trauma model and support the use of highly selective iNOS inhibitors as novel treatments in critical care medicine.

Sign in / Sign up

Export Citation Format

Share Document