scholarly journals Design, synthesis, and evaluation of 4,5,6,7-tetrahydrobenzo[d]thiazole-based novel dual kinase inhibitors of CK2 and GSK3β

MedChemComm ◽  
2018 ◽  
Vol 9 (9) ◽  
pp. 1472-1490 ◽  
Author(s):  
Triveni R. Pardhi ◽  
Manishkumar S. Patel ◽  
V. Sudarsanam ◽  
Kamala K. Vasu
Keyword(s):  
Inhibitory Activity ◽  
Kinase Inhibitors ◽  
Design Synthesis ◽  
Dual Kinase Inhibitors ◽  
Kinase Inhibitory Activity

A rationally designed novel compound (1g) has shown significant dual kinase inhibitory activity against CK2 (1.9 μM) and GSK3β (0.67 μM).

scholarly journals Design, Synthesis and Inhibitory Activity of Photoswitchable RET Kinase Inhibitors

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Rubén Ferreira ◽  
Jesper R. Nilsson ◽  
Carlos Solano ◽  
Joakim Andréasson ◽  
Morten Grøtli
Keyword(s):  
Inhibitory Activity ◽  
Kinase Inhibitors ◽  
Design Synthesis

Activity of ABL Kinase Inhibitors in Two Distinct Models of Imatinib Resistance.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4819-4819
Author(s):  
Nicholas J. Donato ◽  
Ji Wu ◽  
William Bornmann ◽  
Moshe Talpaz
Keyword(s):  
Cell Lines ◽  
Inhibitory Activity ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
K562 Cells ◽  
Mutant Form ◽  
Imatinib Resistance ◽  
Resistant Variant ◽  
Lyn Kinase ◽  
Kinase Inhibitory Activity

Abstract The tyrosine kinase inhibitor imatinib mesylate (Gleevec) is effective in controlling BCR-ABL expressing leukemias but resistance occurs in a small subset of early stage patients and is very common in advanced stage patients. Resistance is associated with overexpression and/or mutations in the BCR-ABL gene but patients are also increasingly reported to fail imatinib therapy while retaining wild-type BCR-ABL expression. To circumvent or overcome resistance novel kinase inhibitors have been synthesized and tested clinically. However, while investigators have designed models to measure and predict activity of novel compounds in mutation-mediated imatinib resistance, other mechanisms of resistance have not been modeled or shown clinical relevance. In this report, the activity of four novel kinase inhibitors (norlotinib, dasatinib, SKI-606, ON012380) was compared in two distinct models of imatinib resistance. These models include cell lines established from natural resistant variant clones selected from imatinib sensitive cell lines and associated with a T315I BCR-ABL mutation (BV-173R) or overexpressed Lyn kinase (K562R). Kinase inhibitory activity in these models was compared to transfectant-based resistance models including BaF3 cells expressing the T315I mutant form of BCR-ABL and overexpression of Lyn kinase in K562 cells. K562R cells were completely resistant to imatinib and norlotinib but highly sensitive to Src/Abl inhibitors (dasatinib, SKI-606) but only partially sensitive to ON012380. Overexpression of Lyn in K562 cells reduced imatinib and norlotinib sensitivity (3-fold) but did not affect sensitivity to the other kinase inhibitors. BV-173R cells expressing the T315I mutant form of BCR-ABL were completely resistant to Abl-selective kinase inhibitors (imatinib, norlotinib) and ~100-fold less sensitive (IC50 ~ 2 microM) to Src/Abl-directed inhibitors (dasatinib, SKI-606) while the non-ATP competitive kinase inhibitor, ON012380, was equally effective against both BV-173 and BV-173R cells. Expression of the T315I mutant form of BCR-ABL in BaF3 cells completely blocked kinase inhibitory activity of all inhibitors except ON012380. IL-3 dependent BaF3 cells were not inhibited by imatinib, norlotinib or SKI-606 but were equally sensitive to ON012380 when compared to IL-3 independent BCR-ABL transfectants. Cellular sensitivity was associated with reduced phosphorylation of BCR-ABL, CrkL and Lyn kinase with all inhibitors except ON012380, which mediated apoptosis in the absence of alterations in tyrosine phosphorylation. Together, our results suggest that imatinib resistant cell models are useful in evaluating the activity of novel kinase inhibitors but need to be carefully interpreted and mechanistically tested. Additional mediators of imatinib resistance need to be defined and modeled so that an appropriate individualized therapy can be applied to most effectively overcome resistant disease.

scholarly journals Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 123
Author(s):  
Elshaymaa I. Elmongy ◽  
Nashwah G. M. Attallah ◽  
Najla Altwaijry ◽  
Manal Mubarak AlKahtani ◽  
Hanan Ali Henidi
Keyword(s):  
Inhibitory Activity ◽  
Kinase Inhibitors ◽  
Apoptotic Cell ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Significant Inhibition ◽  
Design And Synthesis ◽  
Kinase Inhibitory Activity ◽  
Ht 29 ◽  
Mcf 7

This work describes the synthesis and anticancer activity against kinase enzymes of newly designed thiophene and thieno[2,3-d]pyrimidine derivatives, along with their potential to activate autophagic and apoptotic cell death in cancer cells. The designed compounds were scanned for their affinity for kinases. The results were promising with affinity ranges from 46.7% to 13.3%. Molecular docking studies were performed, and the compounds were then screened for their antiproliferative effects. Interestingly, compounds 8 and 5 resulted in higher cytotoxic effects than the reference standard against MCF-7 and HepG-2. The compounds were evaluated for their induction of apoptosis and/or necrosis on HT-29 and HepG-2. Three compounds induced significant early apoptosis compared to untreated control HT-29 cells, and four derivatives were more significant compared to untreated HepG-2 cells. We further investigated the effect of four compounds on the autophagy process within HT-29, HepG-2, and MCF-7 cells with flow cytometry. Similar to the apoptosis results, compound 5 showed the highest autophagic induction among all compounds. The potential inhibitory activity of the synthesized compounds on kinases was assessed. Screened compounds showed inhibition activity ranging from 41.4% to 83.5%. Compounds recorded significant inhibition were further investigated for their specific FLT3 kinase inhibitory activity. Noticeably, Compound 5 exhibited the highest inhibitory activity against FLT3.

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