Inhibitors of the TAM subfamily of tyrosine kinases: Synthesis and biological evaluation

Suárez, Rosa M.; Chevot, Franciane; Cavagnino, Andrea; Saettel, Nicolas; Radvanyi, François; Piguel, Sandrine; Bernard‐Pierrot, Isabelle; Stoven, Véronique; Legraverend, Michel

doi:10.1016/j.ejmech.2012.06.005

Cited by 32 publications

(27 citation statements)

References 38 publications

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“…Substitution of the fluorine atom of the terminal phenyl by a larger O-Met group moiety, as in 13e, leads to a loss of activity. Similar results have already been observed in the case of compound 2, where replacement of F atom by a CF 3 group suppressed inhibition against Tyro3 [19].…”

Section: Biological Resultssupporting

confidence: 86%

“…These two observations indicate that substitution of the pyridine ring by a pyrimidine ring seems to increase the specificity towards the four proteins of the HGFR/TAM family. Such improvement in selectivity is also shared by compound 2, in which the pyridine ring of BMS-777607 was replaced by a purine ring [19].…”

Section: Biological Resultsmentioning

confidence: 95%

“…1) [19]. We highlighted the necessity of the presence of an ether linkage between the purine scaffold and the amidopyridone chain, since changing this linkage led to complete loss of inhibitory activity against all considered kinases in the case of a carbonecarbon bonding and to a reduction of inhibitory activity in the case of an amino bonding, which was complete for Tyro3.…”

Section: Introductionmentioning

confidence: 92%

“…The presence of the amidopyridone group in this lateral chain was found to be important ( Fig. 1) [19].…”

Section: Introductionmentioning

confidence: 98%

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New aminopyrimidine derivatives as inhibitors of the TAM family

Traoré

Cavagnino

Saettel

et al. 2013

European Journal of Medicinal Chemistry

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Section: Biological Resultssupporting

confidence: 86%

Section: Biological Resultsmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 92%

“…The presence of the amidopyridone group in this lateral chain was found to be important ( Fig. 1) [19].…”

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

New aminopyrimidine derivatives as inhibitors of the TAM family

Traoré

Cavagnino

Saettel

et al. 2013

European Journal of Medicinal Chemistry

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“…However, some FDA-approved or clinical molecules, developed to inhibit other kinases, were evaluated against Axl given its interest. Some potent Axl kinase inhibitors in development are described in the literature (45,46). However, as few data are available regarding their selectivity and their application as treatment, we do not describe them here.…”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Axl Kinase as a Key Target for Oncology: Focus on Small Molecule Inhibitors

Feneyrolles¹,

Spenlinhauer²,

Guiet³

et al. 2014

Molecular Cancer Therapeutics

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Receptor tyrosine kinases (RTK) are transmembrane receptors that regulate signal transduction in cells. As a member of the TAM (Tyro-3, Axl, Mer) RTK subfamily, Axl regulates key processes such as cell growth, migration, aggregation, and apoptosis through several pathways. Its overexpression/overactivation has been underlined in several conditions, especially cancers, and in both chemotherapy and targeted therapy sensitivity loss. In this review, we propose to highlight the therapeutic implication of Axl, starting with the pathways it regulates, validating its interest as a therapeutic target, and defining the tools available to develop strategies for its inhibition. We especially focus on small molecule inhibitors, their structure, inhibition profile, and development stages. Mol Cancer Ther; 13(9); 2141-8. Ó2014 AACR.

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Determination of a novel anticancer c‐Met inhibitor LS‐177 in rat plasma and tissues with a validated UPLC‐MS/MS method: application to pharmacokinetics and tissue distribution study

Liu

Jiang

et al. 2014

Biomedical Chromatography

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LS‐177 is a novel small‐molecule kinase inhibitor employed to interrupt the c‐Met signaling pathway. A rapid and sensitive ultraperformance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) method was developed and validated for determination of LS‐177 in rat plasma and tissues. The biosamples were extracted by liquid–liquid extraction with methyl tert‐butyl ether and separated on a C18 column (50 × 4.6 mm, 2.6 µm) using a gradient elution mobile phase consisting of acetonitrile–0.1% formic acid water. Under the optimal conditions, the selectivity of the method was satisfactory with no endogenous interference. The intraday and interday precisions (relative standard deviation) were <10.5% and the accuracy (relative error) was from −12.5 to 12.5% at all quality control levels. Excellent recovery and negligible matrix effects were observed. Stability studies showed that LS‐177 was stable during the preparation and analytical processes. The UPLC‐MS/MS method was successfully applied to pharmacokinetic and tissue distribution studies. The results indicated that there was no significant drug accumulation after multiple‐dose oral administration of LS‐177. The tissue distribution study exhibited significant higher uptakes of LS‐177 in stomach, intestine, lung and liver among all of the tissues. The results in pharmacokinetics and tissue distribution may provide a meaningful basis for clinical application. Copyright © 2014 John Wiley & Sons, Ltd.

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Inhibitors of the TAM subfamily of tyrosine kinases: Synthesis and biological evaluation

Cited by 32 publications

References 38 publications

New aminopyrimidine derivatives as inhibitors of the TAM family

New aminopyrimidine derivatives as inhibitors of the TAM family

Axl Kinase as a Key Target for Oncology: Focus on Small Molecule Inhibitors

Determination of a novel anticancer c‐Met inhibitor LS‐177 in rat plasma and tissues with a validated UPLC‐MS/MS method: application to pharmacokinetics and tissue distribution study

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