The Novel ATP-Competitive Inhibitor of the MET Hepatocyte Growth Factor Receptor EMD1214063 Displays Inhibitory Activity against Selected MET-Mutated Variants

Medová, Michaela; Pochon, Benoît; Streit, Bruno; Blank-Liss, Wieslawa; Francica, Paola; Stroka, Deborah; Keogh, Adrian; Aebersold, Daniel M.; Blaukat, Andree; Bladt, Friedhelm; Zimmer, Yitzhak

doi:10.1158/1535-7163.mct-13-0151

Cited by 27 publications

(29 citation statements)

References 41 publications

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“…In contrast, SAR125844 was inactive on cell lines expressing D1228H and Y1230H mutants, despite biochemical activity of 81 and 204 nmol/L, respectively, suggesting that an affinity of 50 nmol/L or lower is necessary to translate into significant MET inhibition in cell lines. Overall, the activity of SAR125844 on these selected MET mutants is equivalent to the one observed with EMD1214063 (47), and suggests that highly selective type I MET inhibitors might not be active on MET mutants such as Y1230H or D1228H compared with type II nonselective MET inhibitors. Interestingly, in contrast to somatic mutations, germline MET mutations were highly predictive of a response to foretinib in patients with papillary renal cell carcinoma (48).…”

Section: Discussionmentioning

confidence: 83%

The Selective Intravenous Inhibitor of the MET Tyrosine Kinase SAR125844 Inhibits Tumor Growth inMET-Amplified Cancer

Égile

Kenigsberg

Delaisi

et al. 2015

Molecular Cancer Therapeutics

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Activation of the MET/HGF pathway is common in human cancer and is thought to promote tumor initiation, metastasis, angiogenesis, and resistance to diverse therapies. We report here the pharmacologic characterization of the triazolopyridazine derivative SAR125844, a potent and highly selective inhibitor of the MET receptor tyrosine kinase (RTK), for intravenous administration. SAR125844 displayed nanomolar activity against the wild-type kinase (IC 50 value of 4.2 nmol/L) and the M1250T and Y1235D mutants. Broad biochemical profiling revealed that SAR125844 was highly selective for MET kinase. SAR125844 inhibits MET autophosphorylation in cell-based assays in the nanomolar range, and promotes low nanomolar proapoptotic and antiproliferative activities selectively in cell lines with MET gene amplification or pathway addiction. In two MET-amplified human gastric tumor xenograft models, SNU-5 and Hs 746T, intravenous treatment with SAR125844 leads to potent, dose-and time-dependent inhibition of the MET kinase and to significant impact on downstream PI3K/AKT and RAS/MAPK pathways. Long duration of MET kinase inhibition up to 7 days was achieved with a nanosuspension formulation of SAR125844. Daily or every-2-days intravenous treatment of SAR125844 promoted a dose-dependent tumor regression in MET-amplified human gastric cancer models at tolerated doses without treatment-related body weight loss. Our data demonstrated that SAR125844 is a potent and selective MET kinase inhibitor with a favorable preclinical toxicity profile, supporting its clinical development in patients with MET-amplified and MET pathway-addicted tumors.

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Section: Discussionmentioning

confidence: 83%

The Selective Intravenous Inhibitor of the MET Tyrosine Kinase SAR125844 Inhibits Tumor Growth inMET-Amplified Cancer

Égile

Kenigsberg

Delaisi

et al. 2015

Molecular Cancer Therapeutics

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“…We observe this phenomenon, surprisingly not previously reported, both in cells overexpressing the wt MET (human non-small cell lung cancer line H1993) as well as in NIH3T3 cells expressing activating MET mutated variants that overall respond to MET inhibition (MET H1112L, M1268T, V1110I, and V1238I mutations). Contrary, NIH3T3 MET L1213V and NIH3T3 MET Y1248H mutants, that have been previously shown to be resistant to MET small molecule inhibitors [22,23,26], do not respond to MET inhibition by decrease in tyrosine autophosphorylation and also do not display the increase in total MET protein upon treatment with any of the currently used MET inhibitors (Fig. 1).…”

Section: Met Inhibition By Small Molecule Tkis Increases Total Cellulmentioning

confidence: 94%

Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation

et al. 2014

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a b s t r a c tThe MET receptor tyrosine kinase is deregulated primarily via overexpression or point mutations in various human cancers and different strategies for MET inhibition are currently evaluated in clinical trials. We observed by Western blot analysis and by Flow cytometry that MET inhibition by different MET small molecule inhibitors surprisingly increases in a dose-dependent manner total MET levels in treated cells. Mechanistically, this inhibition-related MET accumulation was associated with reduced Tyr1003 phosphorylation and MET physical association with the CBL ubiquitin ligase with concomitant decrease in MET ubiquitination. These data may suggest careful consideration for design of anti-MET clinical protocols. Structured summary of protein interactions:Cbl physically interacts with Met by anti bait coimmunoprecipitation (1, 2)

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“…These results indicate that MET kinase domain mutations may be a mechanism to circumvent MET TKI inhibition. Several earlier studies have demonstrated the ability of MET kinase domain mutations to diminish the efficacy of MET inhibitors (44)(45)(46). It is likely that additional and novel mutations will be identified with the emergence of genomic profiling of recurrent disease through biopsies, circulating tumor cells, and circulating DNA.…”

Section: Reemergence Of Met Kinase Domain Mutations During Resistancementioning

confidence: 99%

MET in human cancer: germline and somatic mutations

Tovar

Graveel

2017

Ann. Transl. Med.

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Since the initial discovery of missense MET mutations in hereditary papillary renal carcinoma (HPRC), activating MET mutations have been identified in a diverse range of human cancers. MET mutations have been identified in several functional domains including the kinase, juxtamembrane, and Sema domains. Studies of these mutations have been invaluable for our understanding of the tumor initiating activity of MET, receptor tyrosine kinase (RTK) recycling and regulation, and mechanisms of resistance to kinase inhibition. These studies also demonstrate that mutationally activated MET plays a significant role in a wide range of cancers and RTKs can promote tumor progression through diverse mechanisms. This review will cover the various MET mutations that have been identified, their mechanism of action, and the significant role that mutationally-activated MET plays in tumor initiation, progression, and therapeutic resistance.

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The Novel ATP-Competitive Inhibitor of the MET Hepatocyte Growth Factor Receptor EMD1214063 Displays Inhibitory Activity against Selected MET-Mutated Variants

Cited by 27 publications

References 41 publications

The Selective Intravenous Inhibitor of the MET Tyrosine Kinase SAR125844 Inhibits Tumor Growth inMET-Amplified Cancer

The Selective Intravenous Inhibitor of the MET Tyrosine Kinase SAR125844 Inhibits Tumor Growth inMET-Amplified Cancer

Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation

MET in human cancer: germline and somatic mutations

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