Inhibitors of the tyrosine kinase EphB4. Part 4: Discovery and optimization of a benzylic alcohol series

Barlaam, Bernard; Ducray, Richard; Brempt, Christine Lambert‐van der; Plé, Patrick; Bardelle, Catherine; Brooks, Nigel; Coleman, Tanya; Cross, Darren A.E.; Kettle, Jason G.; Read, Jon

doi:10.1016/j.bmcl.2011.03.009

Cited by 26 publications

(23 citation statements)

References 16 publications

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“…Finally, it is possible that AZ12489875-002 is not specific to EphB4 but rather targets other RTKs with varying affinities. The original literature on the pharmacokinetics and specificities of EphB4 small molecule inhibitor development [55]–[58] has specifically investigated FGFR1 and VEGFR2 as potential targets of similar molecules. The specificity of most molecular variants for EphB4 is several orders of magnitude greater than for other RTKs, and we therefore feel confident that this agent is indeed relatively specific for EphB4 in our in vitro studies.…”

Section: Discussionmentioning

confidence: 99%

The EphB4 Receptor Tyrosine Kinase Promotes Lung Cancer Growth: A Potential Novel Therapeutic Target

et al. 2013

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Despite progress in locoregional and systemic therapies, patient survival from lung cancer remains a challenge. Receptor tyrosine kinases are frequently implicated in lung cancer pathogenesis, and some tyrosine kinase inhibition strategies have been effective clinically. The EphB4 receptor tyrosine kinase has recently emerged as a potential target in several other cancers. We sought to systematically study the role of EphB4 in lung cancer. Here, we demonstrate that EphB4 is overexpressed 3-fold in lung tumors compared to paired normal tissues and frequently exhibits gene copy number increases in lung cancer. We also show that overexpression of EphB4 promotes cellular proliferation, colony formation, and motility, while EphB4 inhibition reduces cellular viability in vitro, halts the growth of established tumors in mouse xenograft models when used as a single-target strategy, and causes near-complete regression of established tumors when used in combination with paclitaxel. Taken together, these data suggest an important role for EphB4 as a potential novel therapeutic target in lung cancer. Clinical trials investigating the efficacy of anti-EphB4 therapies as well as combination therapy involving EphB4 inhibition may be warranted.

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Section: Discussionmentioning

confidence: 99%

The EphB4 Receptor Tyrosine Kinase Promotes Lung Cancer Growth: A Potential Novel Therapeutic Target

et al. 2013

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“…The displacement of the 4-chloro group of 2,4-dichloropyrimidine by various anilines is already widely reported in the literature. 42,46, 47,48 The hit 1 was resynthesized by hydrolysis (method h , Scheme 1) of the methyl ester 3w , which was prepared from 2a and methyl para -aminobenzoate (method m , Scheme 2). Attempts to directly synthesize 1 from 2a and para -aminobenzoic acid via method a resulted in formation of decarboxylated by-product 3b ( 1 : 3b ca .…”

Section: Introductionmentioning

confidence: 99%

Development of o-Chlorophenyl Substituted Pyrimidines as Exceptionally Potent Aurora Kinase Inhibitors

et al. 2012

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The ortho-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC50 = 6.1 ± 1.0 nM) from in-house screening. Detailed structure activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallography studies revealed that compound 1 is a type-I inhibitor that binds the Aurora kinase active site in a DFG-in conformation. Structure activity guided replacement of the A-ring carboxylic acid with halogens and incorporation of fluorine at the pyrimidine 5-position led to highly potent inhibitors of Aurora A that bind in a DFG-out conformation. B-ring modifications were undertaken to improve the solubility and cell permeability. Compounds such as 9m with water-solubilizing moieties at the para-position of the B-ring inhibited the autophosphorylation of Aurora A in MDA-MB-468 breast cancer cells.

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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%

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

Ebert

Wiemer

Caballero

et al. 2015

Bioorganic & Medicinal Chemistry

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Inhibitors of the tyrosine kinase EphB4. Part 4: Discovery and optimization of a benzylic alcohol series

Cited by 26 publications

References 16 publications

The EphB4 Receptor Tyrosine Kinase Promotes Lung Cancer Growth: A Potential Novel Therapeutic Target

The EphB4 Receptor Tyrosine Kinase Promotes Lung Cancer Growth: A Potential Novel Therapeutic Target

Development of o-Chlorophenyl Substituted Pyrimidines as Exceptionally Potent Aurora Kinase Inhibitors

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

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