5-(2-chloroethyl)-2′-deoxyuridine: A potent and selective inhibitor of herpes viruses in vitro and in vivo

1985 ◽  
Vol 5 ◽  
pp. 21-28 ◽  
Author(s):  
Brigitte Rosenwirth ◽  
Herfried Griengl ◽  
Erich Wanek ◽  
Erik de Clercq
Keyword(s):  
Selective Inhibitor ◽  
Herpes Viruses

scholarly journals THE INTRACELLULAR SITE OF SYNTHESIS OF MITOCHONDRIAL RIBOSOMAL PROTEINS IN NEUROSPORA CRASSA

1972 ◽  
Vol 54 (1) ◽  
pp. 56-74 ◽  
Author(s):  
Paul M. Lizardi ◽  
David J. L. Luck
Keyword(s):  
Protein Synthesis ◽  
Isoelectric Focusing ◽  
Gel Electrophoresis ◽  
Ribosomal Proteins ◽  
Mitochondrial Protein ◽  
Selective Inhibitor ◽  
Mitochondrial Protein Synthesis ◽  
Ribosomal Subunits

The intracellular site of synthesis of mitochondrial ribosomal proteins (MRP) in Neurospora crassa has been investigated using three complementary approaches. (a) Mitochondrial protein synthesis in vitro: Tritium-labeled proteins made by isolated mitochondria were compared to 14C-labeled marker MRP by cofractionation in a two-step procedure involving isoelectric focusing and polyacrylamide gel electrophoresis. Examination of the electrophoretic profiles showed that essentially none of the peaks of in vitro product corresponded exactly to any of the MRP marker peaks. (b) Sensitivity of in vivo MRP synthesis to chloramphenicol: Cells were labeled with leucine-3H in the presence of chloramphenicol, mitochondrial ribosomal subunits were subsequently isolated, and their proteins fractionated by isoelectric focusing followed by gel electrophoresis. The labeling of every single MRP was found to be insensitive to chloramphenicol, a selective inhibitor of mitochondrial protein synthesis. (c) Sensitivity of in vivo MRP synthesis to anisomycin: We have found this antibiotic to be a good selective inhibitor of cytoplasmic protein synthesis in Neurospora. In the presence of anisomycin the labeling of virtually all MRP is inhibited to the same extent as the labeling of cytoplasmic ribosomal proteins. On the basis of these three types of studies we conclude that most if not all 53 structural proteins of mitochondrial ribosomal subunits in Neurospora are synthesized by cytoplasmic ribosomes.

scholarly journals The Effect of a Novel Highly Selective Inhibitor of the Sodium/Calcium Exchanger (NCX) on Cardiac Arrhythmias in In Vitro and In Vivo Experiments

PLoS ONE ◽  
2016 ◽  
Vol 11 (11) ◽  
pp. e0166041 ◽  
Author(s):  
Zsófia Kohajda ◽  
Nikolett Farkas-Morvay ◽  
Norbert Jost ◽  
Norbert Nagy ◽  
Amir Geramipour ◽  
...  
Keyword(s):  
Cardiac Arrhythmias ◽  
Selective Inhibitor ◽  
Sodium Calcium Exchanger ◽  
In Vivo Experiments ◽  
Sodium Calcium

scholarly journals SHC014748M, a Novel Selective Inhibitor of PI3Kδ, Demonstrates Promising Pre-Clinical Antitumor Activity in B Cell Lymphomas and CLL

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5306-5306
Author(s):  
Lei Fan ◽  
Chao Wang ◽  
Zhiqiang Wang ◽  
Xian Zhang ◽  
Lei Cao ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
B Cell ◽  
Cell Lines ◽  
Xenograft Model ◽  
Selective Inhibitor ◽  
Lymphoma Cell ◽  
Class I ◽  
B Cell Lymphomas

Introduction : PI3Kδ, one of the class I PI3Ks, is found expressed primarily in leukocytes and plays an essential role in B-cell development and function. Here, we comprehensively evaluated the in vitro and in vivo antitumor activity and the underlying mechanism of SHC014748M, an oral selective inhibitor of PI3Kδ under Phase I clinical evaluation. Methods : Biochemical and cell-based assays were used to measure compound potency and selectivity in lymphoma cell lines as well as primary CLL cells, and PI3K/AKT pathway was measured by Western blot assay, Alphalisa and Elisa. Xenograft model was carried out to validate in-vivo antitumor potency of the compound. Besides, chemokines and cytokines derived from blood samples of patients were also detected. Results: SHC014748M was 125- to 306-fold more selective for PI3Kδ inhibition relative to other class I PI3K enzymes and showed in vitro activity in most of 23 B lymphoma cell lines. We identified that SHC014748M treatment resulted in a 3.1- to 5.5-fold increase in annexin V/7-ADD staining, indicating a significant apoptosis induction. SHC014748M inhibited phosphorylation of AKT, targets downstream of PI3Kδ, in lymphoma cells. Among the 15 primary CLL cells, the 50% inhibitory concentration (IC50) of SHC014748M varies from 850 nM to 37040 nM respectively and expression of phosphorylation AKT decreased to the normal levels in the presence of SHC014748M or positive control, Idelalisib. In-vivo study revealed that SHC014748M significantly reduced lymphoma cell growth in the treatment group compared with control mice. CCL4, CCL17, CCL22 and CXCL13 derived from patients decreased sharply after SHC014748M treatment. Conclusion: According to the results, SHC014748M appeared to be a novel promising compound in the treatment of B cell lymphomas and CLL. Disclosures Wang: Nanjing Sanhome Pharmaceutical Co., Ltd.: Employment. Wang:Nanjing Sanhome Pharmaceutical Co., Ltd.: Employment. Zhang:Nanjing Sanhome Pharmaceutical Co., Ltd.: Employment.

ACY-1215, a First-In-Class Selective Inhibitor Of HDAC6, Demonstrates Significant Synergy With Immunomodulatory Drugs (IMiDs) In Preclinical Models Of Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1952-1952 ◽  
Author(s):  
Steven N Quayle ◽  
Simon S Jones
Keyword(s):  
Selective Inhibitor ◽  
Clinical Development ◽  
Clinical Activity ◽  
Preclinical Models ◽  
Employment Equity ◽  
Phase Ib ◽  
Equity Ownership ◽  
Ongoing Phase

Abstract Histone deacetylase (HDAC) enzymes represent attractive therapeutic targets in multiple myeloma, but unfortunately non-selective HDAC inhibitors have led to dose-limiting toxicities in patients. ACY-1215 is a first generation, orally available HDAC inhibitor that is 11-fold selective for HDAC6, and synergizes in vitro and in vivo with bortezomib in preclinical models of MM without inducing unfavorable toxicities (Blood, 20[210]: 4061). Ongoing Phase Ib clinical trials with ACY-1215 have thus far confirmed an exceptional safety and tolerability profile (Raje, et al, EHA, 2013). The IMiD class of drugs, including lenalidomide and pomalidomide, exhibit striking anti-myeloma properties in a variety of MM models, and have demonstrated significant clinical activity in MM patients. Prior studies have shown clinical activity of a combination of the non-selective HDAC inhibitor vorinostat with lenalidomide and dexamethasone in myeloma patients (Richter, et al, ASH, 2011). However, many patients experienced significant toxicities with this regimen that significantly limits its clinical utility. In support of our ongoing clinical development program for ACY-1215 in MM, we show here that combining ACY-1215 with either lenalidomide or pomalidomide leads to synergistic decreases in the viability of MM cells in vitro. The relevance of inhibition of HDAC6 to this synergistic effect was validated by demonstrating synergistic interactions of either IMiD molecule with ACY-775, which is more than 300-fold selective for HDAC6 over class I HDAC’s. Further, the combination of ACY-1215, lenalidomide, and dexamethasone was well tolerated in vivo with no overt evidence of toxicity, and combination efficacy studies with this combination are now ongoing in models of MM. By demonstrating that a selective inhibitor of HDAC6 synergizes with IMiD’s while maintaining an improved safety profile, these results provided a rational basis for the clinical development of the orally available combination of ACY-1215 and lenalidomide plus dexamethasone in an ongoing Phase Ib clinical trial (NCT01583283) for the treatment of MM. Disclosures: Quayle: Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Jones:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership.

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