Pyrimidoaminotropanes as Potent, Selective, and Efficacious Small Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin (mTOR)

2013 ◽  
Vol 56 (7) ◽  
pp. 3090-3101 ◽  
Author(s):  
Anthony A. Estrada ◽  
Daniel G. Shore ◽  
Elizabeth Blackwood ◽  
Yung-Hsiang Chen ◽  
Gauri Deshmukh ◽  
...  
Keyword(s):  
Small Molecule ◽  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin

Synthesis and biological activity of new 2,4,6-trisubstituted triazines as potential phosphoinositide 3-kinase inhibitors

2020 ◽  
Vol 44 (7-8) ◽  
pp. 393-402
Author(s):  
Minhang Xin ◽  
Hui-Yan Wang ◽  
Hao Zhang ◽  
Ying Shen ◽  
San-Qi Zhang
Keyword(s):  
Biological Activity ◽  
Anticancer Drugs ◽  
Antiproliferative Activity ◽  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Hct 116 ◽  
Phosphoinositide 3 Kinase ◽  
New Anticancer Drugs ◽  
Mcf 7

Twenty-five novel 2,4,6-trisubstituted triazines were synthesized and biologically evaluated. Most of the compounds synthesized showed good antiproliferative activity against HCT-116 and MCF-7. Compounds B18 and B19 showed the best antiproliferative activity. Further study showed B18 and B19 inhibited four phosphoinositide 3-kinase isoforms and mammalian target of rapamycin with good potency. These results demonstrate that 2,4,6-trisubstituted triazines are potentially useful phosphoinositide 3-kinase inhibitors for the development of new anticancer drugs.

scholarly journals Synchronous inhibition of mTOR and VEGF/NRP1 axis impedes tumor growth and metastasis in renal cancer

2019 ◽  
Vol 3 (1) ◽  
Author(s):  
Krishnendu Pal ◽  
Vijay Sagar Madamsetty ◽  
Shamit Kumar Dutta ◽  
Enfeng Wang ◽  
Ramcharan Singh Angom ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Vegf Receptor ◽  
Vascular Permeability Factor ◽  
Cell Renal Cell Carcinoma ◽  
Antiangiogenic Therapies

AbstractClear cell renal cell carcinoma (ccRCC) is known for its highly vascular phenotype which is associated with elevated expression of vascular endothelial growth factor A (VEGF), also known as vascular permeability factor (VPF). Accordingly, VEGF has been an attractive target for antiangiogenic therapies in ccRCC. Two major strategies have hitherto been utilized for VEGF-targeted antiangiogenic therapies: targeting VEGF by antibodies, ligand traps or aptamers, and targeting the VEGF receptor signaling via antibodies or small-molecule tyrosine-kinase inhibitors (TKIs). In the present article we utilized two entirely different approaches: targeting mammalian target of rapamycin (mTOR) pathway that is known to be involved in VEGF synthesis, and disruption of VEGF/Neuroplin-1 (NRP1) axis that is known to activate proangiogenic and pro-tumorigenic signaling in endothelial and tumor cells, respectively. Everolimus (E) and a small-molecule inhibitor EG00229 (G) were used for the inhibition of mTOR and the disruption of VEGF/NRP1 axis, respectively. We also exploited a liposomal formulation decorated with a proprietary tumor-targeting-peptide (TTP) to simultaneously deliver these two agents in a tumor-targeted manner. The TTP-liposomes encapsulating both Everolimus and EG00229 (EG-L) demonstrated higher in vitro and in vivo growth retardation than the single drug-loaded liposomes (E-L and G-L) in two different ccRCC models and led to a noticeable reduction in lung metastasis in vivo. In addition, EG-L displayed remarkable inhibition of tumor growth in a highly aggressive syngeneic immune-competent mouse model of ccRCC developed in Balb/c mice. Taken together, this study demonstrates an effective approach to achieve improved therapeutic outcome in ccRCC.

Immunsuppressiva - Wirkungen, Nebenwirkungen und Interaktionen

2011 ◽  
Vol 68 (12) ◽  
pp. 679-686 ◽  
Author(s):  
Fabien Stucker ◽  
Daniel Ackermann
Keyword(s):  
Small Molecule ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Intravenöse Immunglobuline ◽  
Small Molecule Drugs

Immunsuppressiva sollen die Abstoßung des gespendeten Organs durch den Empfänger verhindern. Die Kenntnis der Wirkmechanismen der Immunsuppressiva sowie deren Nebenwirkungen und Interaktionen mit anderen Medikamenten ist Grundvoraussetzung für die Behandlung von transplantierten Patienten. Immunsuppression kann entweder durch eine Depletion, durch Blockierung der Aktivierung oder durch eine verminderte Proliferation von Lymphozyten erreicht werden. Immunsuppressiva umfassen sogenannte «small-molecule drugs», depletierende und nicht depletierende Antikörper, Fusionsproteine, intravenöse Immunglobuline und Glukokortikoide. «Small-molecule drugs» sind: Calcineurininhibitoren, Inhibitoren des «mammalian Target-of-Rapamycin», der Nukleotidsynthese sowie Azathioprin. Die Wirkmechanismen der am meisten verwendeten Immunsuppressiva werden in dieser Übersichtarbeit erklärt und ihre positiven und negativen Nebenwirkungen aufgezählt. Wirkung und Nebenwirkungen des Fusionsproteins Belatacept werden besonders behandelt. Interaktionen mit häufig verwendeten Medikamenten werden tabellarisch aufgelistet.

Roles of the mammalian target of rapamycin, mTOR, in controlling ribosome biogenesis and protein synthesis

2012 ◽  
Vol 40 (1) ◽  
pp. 168-172 ◽  
Author(s):  
Valentina Iadevaia ◽  
Yilin Huo ◽  
Ze Zhang ◽  
Leonard J. Foster ◽  
Christopher G. Proud
Keyword(s):  
Protein Synthesis ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Energy Status ◽  
Stable Isotope Labelling ◽  
Mtor Kinase ◽  
The Impact

mTORC1 (mammalian target of rapamycin complex 1) is controlled by diverse signals (e.g. hormones, growth factors, nutrients and cellular energy status) and regulates a range of processes including anabolic metabolism, cell growth and cell division. We have studied the impact of inhibiting mTOR on protein synthesis in human cells. Partial inhibition of mTORC1 by rapamycin has only a limited impact on protein synthesis, but inhibiting mTOR kinase activity causes much greater inhibition of protein synthesis. Using a pulsed stable-isotope-labelling technique, we show that the rapamycin and mTOR (mammalian target of rapamycin) kinase inhibitors have differential effects on the synthesis of specific proteins. In particular, the synthesis of proteins encoded by mRNAs that have a 5′-terminal pyrimidine tract is strongly inhibited by mTOR kinase inhibitors. Many of these mRNAs encode ribosomal proteins. mTORC1 also promotes the synthesis of rRNA, although the mechanisms involved remain to be clarified. We found that mTORC1 also regulates the processing of the precursors of rRNA. mTORC1 thus co-ordinates several steps in ribosome biogenesis.

Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115

2015 ◽  
Vol 58 (14) ◽  
pp. 5599-5608 ◽  
Author(s):  
Deborah S. Mortensen ◽  
Sophie M. Perrin-Ninkovic ◽  
Graziella Shevlin ◽  
Jan Elsner ◽  
Jingjing Zhao ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Mtor Kinase

scholarly journals Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling

2016 ◽  
Vol 291 (10) ◽  
pp. 5221-5233 ◽  
Author(s):  
Rory T. Coffey ◽  
Yuntao Shi ◽  
Marcus J. C. Long ◽  
Michael T. Marr ◽  
Lizbeth Hedstrom
Keyword(s):  
Small Molecule ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Small Molecule Inhibition ◽  
Mtorc1 Signaling
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