Inhibitors of the tyrosine kinase EphB4. Part 1: Structure-based design and optimization of a series of 2,4-bis-anilinopyrimidines

Bardelle, Catherine; Cross, Darren A.E.; Davenport, Sara; Kettle, Jason G.; Ko, Eun-Jung; Leach, Andrew G.; Mortlock, Andrew A.; Read, Jon; Roberts, Nicola; Robins, P. A.; Williams, Emma J.

doi:10.1016/j.bmcl.2008.04.015

Cited by 54 publications

(50 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

“…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). When the benzodioxole is replaced with other moieties, this dramatically reduces effectiveness against EphB4 (4).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Kamau

Meehan

Lavine

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…In addition, using ligands for multiple "targets" help ensure some chemical diversity in the decoy library. Specific inhibitors with K i or IC 50 values below 10 nM were obtained for the following targets (number of inhibitors in parentheses): neuraminidase (25), metabotropic glutamate receptor isoforms 1-8 (213), monoamine oxidase A and B (199), VEGFR (44), and EphB4 (39) [16][17][18][19]. 3D structures for these decoy ligands were generated using MOE (www.chemcomp.com) from available 2D SDF structures or canonical SMILES (simplified molecular-input lineentry system) strings.…”

Section: Decoy Library For Virtual Screeningmentioning

confidence: 99%

Identifying potential selective fluorescent probes for cancer-associated protein carbonic anhydrase IX using a computational approach

Kamstra

Floriano

2014

Journal of Molecular Graphics and Modelling

View full text Add to dashboard Cite

“…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%

Development of indazolylpyrimidine derivatives as high-affine EphB4 receptor ligands and potential PET radiotracers

Ebert

Wiemer

Caballero

et al. 2015

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Inhibitors of the tyrosine kinase EphB4. Part 1: Structure-based design and optimization of a series of 2,4-bis-anilinopyrimidines

Cited by 54 publications

References 16 publications

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

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

Identifying potential selective fluorescent probes for cancer-associated protein carbonic anhydrase IX using a computational approach

Development of indazolylpyrimidine derivatives as high-affine EphB4 receptor ligands and potential PET radiotracers

Contact Info

Product

Resources

About