Novel thienopyrimidine and thiazolopyrimidine kinase inhibitors with activity against Tie-2 in vitro and in vivo

Luke, Richard; Ballard, Peter; Buttar, David; Campbell, Leonie; Curwen, Jon; Emery, Steve; Griffen, Alison M.; Hassall, Lorraine; Hayter, Barry R.; Jones, Cliff; McCoull, William; Mellor, Martine J.; Swain, Mike L.; Tucker, J.A.

doi:10.1016/j.bmcl.2009.10.001

Cited by 31 publications

(25 citation statements)

References 16 publications

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“…[27,28]The receptor tyrosine kinase Tie-2 is mainly expressed in the vascular endothelium and is involved in vessel branching, remodeling,sprouting, maturation, and stability. [29,30] A novel class of thieno[2,3-d]pyrimidines has been discovered by Luke et al [31] as potent inhibitors of Tie-2compounds 11-15. The thienopyrimidine 11was reasonably potent and selective.…”

Section: Tiementioning

confidence: 98%

Thieno[2,3-d]pyrimidine based derivatives as kinase inhibitors and anticancer agents

Elrazaz

Serya

Ismail

et al. 2015

Future Journal of Pharmaceutical Sciences

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Please cite this article as: Elrazaz EZ, Serya RAT, Ismail NSM, Abou El Ella DA, Abouzid KAM, Thieno[2,3-d]pyrimidine based derivatives as kinase inhibitors and anticancer agents, Future Journal of Pharmaceutical sciences (2015), AbstractThienopyrimidines are fused heterocyclic ring systems; structurally resemble purines, exerting pharmacological potential in different aspects. They are known to play a crucial role in various disease conditions. Thieno[2,3-d]pyrimidine derivatives have been explored fortheir inhibitory activities towards various protein kinase enzymes. The present review is a compilation on chemical synthesis and biological anticancer significance, via inhibition of specific protein kinase enzymes, including structure-activity relationships of thieno[2,3-d]pyrimidines derivatives reported to date.

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Section: Tiementioning

confidence: 98%

Thieno[2,3-d]pyrimidine based derivatives as kinase inhibitors and anticancer agents

Elrazaz

Serya

Ismail

et al. 2015

Future Journal of Pharmaceutical Sciences

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“…At present, two DFG-in structures (Type-I) of Tie-2 complexes (PDB entries: 2WQB and 3L8P)3334 are available in RCSB Protein Data Bank35. Both crystal structures were firstly assessed for their ability to distinguish the known inhibitors from non-inhibitors of Tie-2 using two different scoring modes of docking (Glide SP and XP).…”

Section: Resultsmentioning

confidence: 99%

In Silico Exploration for Novel Type-I Inhibitors of Tie-2/TEK: The Performance of Different Selection Strategy in Selecting Virtual Screening Candidates

Pan

Sun

Liu

et al. 2016

Sci Rep

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The receptor tyrosine kinase Tie-2 is involved in vessel remodeling and maturation, and has been regarded as a potential target for the treatment of various solid tumors. The absence of novel, potent and selective inhibitors severely hampers the understanding of the therapeutic potential of Tie-2. In the present work, we describe the discovery of novel type-I inhibitors of Tie-2 by structure-based virtual screening. Preliminary SAR was also performed based on one active compound, and several novel inhibitors with low micro-molar affinity were discovered. To directly compare the efficiency between different filtering strategies in selecting VS candidates, two methods were separately carried out to screen the same chemical library, and the selected VS candidates were then experimentally assessed by in vitro enzymatic assays. The results demonstrate that the hit rate is improved when stricter drug-likeness criteria and less number of molecules for clustering analysis are used, and meanwhile, the molecular diversity of the compounds still maintains. As a case study of TIE-2, the information presented in this work underscores the importance of selecting an appropriate selection strategy in VS campaign, and the novel inhibitors identified and the detailed binding modes of action provide a starting point for further hit-to-lead optimization process.

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“…On the other hand, the treatment of compound 1 with phenyl isothiocyanate in dry benzene yielded the corresponding thioureido derivative 4 which, in turn, converted to thieno [2,3-d] pyrimidinone 5 by treatment with hydrazine hydrate in ethanolic solution. The reaction of compound 5 with acetic anhydride afforded 6-(4-nitrophenoxy)-2,7-dimethyl-3-phenylthieno [2,3-d] [1,2,4]triazolo [1,5-a]pyrimidin-8-(3H)-one (6). Moreover, the reaction of the ortho-amino ester 1 with hydrazine hydrate in ethanol afforded the carbohydrazide derivative 7.…”

Section: Resultsmentioning

confidence: 99%

“…They play important roles as antihypertensive, antipyretic, antiviral and anti-inflammatory drugs. [1][2][3][4][5][6][7][8] In addition, triazine and triazole compounds possess diverse biological uses such as antifungals, insecticides, herbicides and plant growth regulators. [9][10][11][12][13][14][15] Encouraged by these findings and as a continuation of our studies into the synthesis of a variety of heterocyclic systems of biological interest, [16][17][18] we have found that ethyl 2-aminothiophene-3-carboxylate 1 is a versatile, readily accessible building block for the synthesis of new series of fused thienopyrimidine derivatives.…”

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confidence: 99%

Efficient Synthesis of Thieno[2,3-d]Pyrimidines and Related Fused Systems

Aly

Behalo

2010

Journal of Chemical Research

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Novel thienopyrimidine and thiazolopyrimidine kinase inhibitors with activity against Tie-2 in vitro and in vivo

Cited by 31 publications

References 16 publications

Thieno[2,3-d]pyrimidine based derivatives as kinase inhibitors and anticancer agents

Thieno[2,3-d]pyrimidine based derivatives as kinase inhibitors and anticancer agents

In Silico Exploration for Novel Type-I Inhibitors of Tie-2/TEK: The Performance of Different Selection Strategy in Selecting Virtual Screening Candidates

Efficient Synthesis of Thieno[2,3-d]Pyrimidines and Related Fused Systems

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