Inhibitors of the tyrosine kinase EphB4. Part 3: Identification of non-benzodioxole-based kinase inhibitors

Bardelle, Catherine; Barlaam, Bernard; Brooks, Nigel; Coleman, Tanya; Cross, Darren A.E.; Ducray, Richard; Green, Isabelle; Brempt, Christine Lambert‐van der; Olivier, Annie; Read, Jon

doi:10.1016/j.bmcl.2010.08.100

Cited by 34 publications

(33 citation statements)

References 25 publications

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“…One strategy for targeting EPHB4 is inhibition of its kinase activity. To determine the extent to which inhibition of the EPHB4 kinase, like RNAi-mediated EPHB4 depletion, is selectively toxic to colon tumor cells, we measured viability in HCECs and a panel of colon tumor cell lines treated for 72 h with increasing doses of an EPHB4 kinase inhibitor, AZ12672857 (AZ2857) (59). The EC 50 for each cell line was determined from four independent experiments using a nonlinear curve fitted with a variable slope (Fig.…”

Section: Resultsmentioning

confidence: 99%

KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors

McCall

Gehring

Clymer

et al. 2016

Molecular and Cellular Biology

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Section: Resultsmentioning

confidence: 99%

KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors

McCall

Gehring

Clymer

et al. 2016

Molecular and Cellular Biology

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“…Benzodioxole-containing compounds have been implicated as inhibitors of eukaryotic protein kinases, and their effects on the receptor tyrosine kinase EphB4 have been studied in great detail (4)(5)(6). Benzodioxole-containing compounds were found to be highly effective at inhibiting EphB4 activity in vitro, and cocrystals with EphB4 reveal that the benzodioxole moiety interacts with the gatekeeper threonine residue in the kinase (6).…”

Section: Discussionmentioning

confidence: 99%

A Novel Benzodioxole-Containing Inhibitor of Toxoplasma gondii Growth Alters the Parasite Cell Cycle

Kamau

Meehan

Lavine

et al. 2011

Antimicrob Agents Chemother

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Toxoplasma gondii is an obligate intracellular parasite that can cause disease in the developing fetus and in immunocompromised humans. Infections can last for the life of the individual, and to date there are no drugs that eliminate the chronic cyst stages that are characteristic of this parasite. In an effort to identify new chemical scaffolds that could form the basis for new therapeutics, we carried out a chemoinformatic screen for compounds that had the potential to interact with members of a superfamily of parasite-secreted kinases and assayed them for growth inhibition in vitro. Of 17 candidate compounds, we identified one with potent antiparasitic activity. The compound has a 50% inhibitory concentration (IC 50 ) of ϳ2 nM, and structurefunction analyses implicate the benzodioxole moiety in its action. The compound does not appear to be cytotoxic to host cells. Using microarray analyses of both parasites and host cells treated with the compound, we found that the levels of very few host cell transcripts are altered by the compound, while a large number of parasite transcripts have a different abundance after compound treatment. Gene ontology analyses of parasite transcripts with a different abundance revealed an enrichment of cell cycle-related genes, suggesting that the compound alters progression of the parasite through the cell cycle. Assaying the nuclear content of treated parasites demonstrated that compound treatment significantly increased the percentage of parasites in the S/M phase of the cell cycle compared to controls. This compound and its analogs represent a novel scaffold with antiparasitic activity.

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“…Due to the favorable chemical and biological properties, small organic inhibitors (e.g., IIIa or IV) published by Bardelle et al are the basis of our research (Scheme 1). [22][23][24][25] Recently, the novel fluorine-18-containing radiotracer IIIb based on the benzodioxolylpyrimidine structural motif was developed http://dx.doi.org/10.1016/j.bmc.2015.06.040 0968-0896/Ó 2015 Elsevier Ltd. All rights reserved. and analyzed via in vitro and in vivo studies.…”

Section: Introductionmentioning

confidence: 99%