Effektivität eines src Kinase Inhibitors in Kombination mit Chemotherapie gegen das orthotop im Nacktmausmodell wachsende humane Pankreaskarzinom

A series of 6- and 8-cinnamoylchromen-2-one and dihydropyranochromen-2-one derivatives were synthesized and their antiproliferative activities were evaluated against three human cancer cell lines, i.e., ovarian adenocarcinoma (SK-OV-3), leukemia (CCRF-CEM), and breast carcinoma (MCF-7). In general, 8-cinnamoylchromen-2-one derivatives were found to have higher antiproliferative activity against the cancer cells when compared with 6-cinnamoyl analogues. Among all of the hybrid chromen-2-one − chalcone/flavanone compounds, a 7-hydroxy-8-cinnamoylchromen-2-one derivative 35 was found to be consistently active against all the cancer cell lines and inhibited the cell proliferation of SK-OV-3, CCRF-CEM, and MCF-7 by 63%, 50%, and 43%, respectively, at a concentration of 50 μmol/L after 72 h of incubation. This compound also exhibited the highest Src kinase inhibition (IC50 = 14.5 μmol/L). Structure−activity relationship studies provided insights for designing the next generation of chromen-2-one − chalcone hybrid prototypes and the development of new leads as anticancer agents and (or) Src kinase inhibitors.

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Biochemical and cellular effects of c-Src kinase-selective pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors

Biochemical Pharmacology ◽

10.1016/s0006-2952(00)00405-6 ◽

2000 ◽

Vol 60 (7) ◽

pp. 885-898 ◽

Cited By ~ 83

Author(s):

Alan J Kraker ◽

Brian G Hartl ◽

Aneesa M Amar ◽

Mark R Barvian ◽

H.D.Hollis Showalter ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Src Kinase ◽

Cellular Effects

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Cyclic peptides containing tryptophan and arginine as Src kinase inhibitors

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2013.03.124 ◽

2013 ◽

Vol 23 (11) ◽

pp. 3230-3234 ◽

Cited By ~ 9

Author(s):

Amir Nasrolahi Shirazi ◽

Rakesh Kumar Tiwari ◽

Alex Brown ◽

Dindyal Mandal ◽

Gongqin Sun ◽

...

Keyword(s):

Cyclic Peptides ◽

Kinase Inhibitors ◽

Src Kinase

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Src kinase inhibitors: an emerging therapeutic treatment option for prostate cancer

Expert Opinion on Investigational Drugs ◽

10.1517/13543781003789388 ◽

2010 ◽

Vol 19 (5) ◽

pp. 605-614 ◽

Cited By ~ 25

Author(s):

Joanne Edwards

Keyword(s):

Prostate Cancer ◽

Treatment Option ◽

Kinase Inhibitors ◽

Src Kinase ◽

Therapeutic Treatment

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Substituted 4-Anilino-7-phenyl-3-quinolinecarbonitriles as Src Kinase Inhibitors.

ChemInform ◽

10.1002/chin.200308219 ◽

2003 ◽

Vol 34 (8) ◽

Author(s):

Dan Berger ◽

Minu Dutia ◽

Dennis Powell ◽

Allan Wissner ◽

Frenel DeMorin ◽

...

Keyword(s):

Kinase Inhibitors ◽

Src Kinase

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Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate–resistant Bcr-Abl kinases

Blood ◽

10.1182/blood-2002-01-0288 ◽

2003 ◽

Vol 101 (2) ◽

pp. 664-672 ◽

Cited By ~ 100

Author(s):

Markus Warmuth ◽

Nicola Simon ◽

Olga Mitina ◽

Ruth Mathes ◽

Doriano Fabbro ◽

...

Keyword(s):

Imatinib Mesylate ◽

Kinase Inhibitors ◽

Clonal Evolution ◽

Src Kinase ◽

Dependent Manner ◽

Binding Modes ◽

Concentration Dependent Manner ◽

Growth And Survival ◽

Abl Kinase ◽

In Cells

The leukemogenic tyrosine kinase Bcr-Abl contains a highly conserved inhibitor-binding pocket (IBP), which serves as a binding site for imatinib mesylate. Mutations at the IBP may lead to resistance of the Abl kinase against imatinib mesylate. To examine the mechanisms of imatinib mesylate binding and resistance in more detail, we created several point mutations at amino acid positions 315 and 380 of Abl, blocking the access to the IBP and rendering Bcr-Abl imatinib mesylate–resistant. Moreover, introduction of a mutation destabilizing the inactive conformation of Abl (Asp276Ser/Glu279Ser) also led to imatinib mesylate resistance, suggesting that the inhibitor required inactivation of the kinase prior to binding. These Bcr-Abl mutants were then used to evaluate the binding mode and specificity of 2 compounds, PP1 and CGP76030, originally characterized as Src kinase inhibitors. Both compounds inhibited Bcr-Abl in a concentration-dependent manner by overlapping binding modes. However, in contrast to imatinib mesylate, PP1 and CGP76030 blocked cell growth and survival in cells expressing various inhibitor-resistant Abl mutants. Studies on the potential signaling mechanisms demonstrated that in cells expressing inhibitor-resistant Bcr-Abl mutants, PP1 and CGP76030 inhibited the activity of Src family tyrosine kinases and Akt but not signal transducer and activator of transcription–5 (STAT5) and JUN kinase (Jnk). The results suggest that the use of Src kinase inhibitors is a potential strategy to prevent or overcome clonal evolution of imatinib mesylate resistance in Bcr-Abl+ leukemia.

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