Cell Lines Expressing Recombinant Transmembrane Domain–Activated Receptor Kinases as Tools for Drug Discovery

Weber, Holger; Müller, Daniel; Müller, Mélanie; Ortiz, Alexandra M.; Birkle, Marianne; Umber, Sarah; Ketterer, Constance; Siedentopf, Oliver; Feger, Daniel; Totzke, Frank; Kubbutat, Michael H.G.; Schäechtele, Christoph; Ballmer-Hofer, Kurt; Ehlert, Jan E.; Graeser, Ralph

doi:10.1177/1087057114552414

Cited by 3 publications

(2 citation statements)

References 33 publications

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“…MET mutations involving the A-loop residues D1228 and Y1230 that confer resistance to type I MET inhibitors have now been described in model systems and multiple patients (18)(19)(20). Because of the differential engagement of the A-loop, type I and type II MET inhibitors are predicted to be differentially susceptible to certain active site mutations implicated in drug resistance (19,(24)(25)(26). Thus, type II inhibitors are predicted to be effective against certain MET mutations implicated in resistance to type I inhibitors enabling a sequential treatment strategy in the setting of target-mediated drug resistance.…”

Section: Introductionmentioning

confidence: 99%

Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models

Engstrom

Aranda

Lee

et al. 2017

Clinical Cancer Research

117

133

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Purpose: MET exon 14 deletion (METex14 del) mutations represent a novel class of non-small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 delpositive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors.Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials.Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutationpositive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA.Conclusions: Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. Clin Cancer Res; 23(21); 6661-72. Ó2017 AACR.

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Section: Introductionmentioning

confidence: 99%

Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models

Engstrom

Aranda

Lee

et al. 2017

Clinical Cancer Research

117

133

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“…In addition, the extended chain compounds 8a–8g also performed moderate antiproliferative activities. In general, compound 4c was the best in all the target compounds, which was potentially developing into an anti-tumour reagent as the reports in literature 35–38 .…”

Section: Resultsmentioning

confidence: 88%

Design, synthesis and biological evaluation of a series of dianilinopyrimidines as EGFR inhibitors

Yan

Wang

Liu

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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This paper described our efforts to develop dianilinopyrimidines as novel EGFR inhibitors. All the target compounds were tested for inhibitory effects against wild type EGFR (EGFR wt ) and three tumour cells, including A549, PC-3, and HepG2. Some of the compounds performed well in antitumor activities. Especially, compound 4c 2-((2-((4-(3-fluorobenzamido)phenyl)amino)-5-(trifluoromethyl) pyrimidin-4-yl)amino)- N -methylthiophene-3-carboxamide showed higher anti-tumour activities than Gefitinib. The IC 50 values of compound 4c against A549, PC-3, and HepG2. reached 0.56 μM, 2.46 μM, and 2.21 μM, respectively. In addition, further studies indicated that compound 4c could induce apoptosis against A549 cells and arrest A549 cells in the G2/M phase. Molecular docking studies showed that compound 4c could closely interact with EGFR. Generally, compound 4c was the potential for developing into an anti-tumour drug.

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MET receptor in oncology: From biomarker to therapeutic target

Malik

Mambetsariev

Fricke

et al. 2020

Advances in Cancer Research

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Cell Lines Expressing Recombinant Transmembrane Domain–Activated Receptor Kinases as Tools for Drug Discovery

Cited by 3 publications

References 33 publications

Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models

Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models

Design, synthesis and biological evaluation of a series of dianilinopyrimidines as EGFR inhibitors

MET receptor in oncology: From biomarker to therapeutic target

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