Differential inhibition sensitivities of MET mutants to the small molecule inhibitor SU11274

Yitzhak Zimmer; Angelina V. Vaseva; Michaela Medová; Bruno Streit; Wieslawa Blank-Liss; Richard H. Greiner; Nikolaus Schiering; Daniel M. Aebersold

doi:10.1016/j.canlet.2009.08.017

Differential inhibition sensitivities of MET mutants to the small molecule inhibitor SU11274

Yitzhak Zimmer, Angelina V. Vaseva, Michaela Medová, Bruno Streit, Wieslawa Blank-Liss, Richard H. Greiner, Nikolaus Schiering, Daniel M. Aebersold

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

Point mutations emerge as one of the rate-limiting steps in tumor response to small molecule inhibitors of protein kinases. Here we characterized the response of the MET mutated variants, V1110I, V1238I, V1206L and H1112L to the small molecule SU11274. Our results reveal a distinct inhibition pattern of the four mutations with IC₅₀ values for autophosphorylation inhibition ranging between 0.15 and 1.5 μM. Differences were further seen on the ability of SU11274 to inhibit phosphorylation of downstream MET transducers such as AKT, ERK, PLCγ and STAT3 and a variety of MET-dependent biological endpoints. In all the assays, H1112L was the most sensitive to SU11274, while V1206L was less affected under the used concentration range. The differences in responses to SU11274 are discussed based on a structural model of the MET kinase domain.

Original language	English (US)
Pages (from-to)	228-236
Number of pages	9
Journal	Cancer Letters
Volume	289
Issue number	2
DOIs	https://doi.org/10.1016/j.canlet.2009.08.017
State	Published - Mar 28 2010
Externally published	Yes

Keywords

Drug resistance
MET
Point mutations
Receptor tyrosine kinases
SU11274

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.canlet.2009.08.017

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title = "Differential inhibition sensitivities of MET mutants to the small molecule inhibitor SU11274",

abstract = "Point mutations emerge as one of the rate-limiting steps in tumor response to small molecule inhibitors of protein kinases. Here we characterized the response of the MET mutated variants, V1110I, V1238I, V1206L and H1112L to the small molecule SU11274. Our results reveal a distinct inhibition pattern of the four mutations with IC50 values for autophosphorylation inhibition ranging between 0.15 and 1.5 μM. Differences were further seen on the ability of SU11274 to inhibit phosphorylation of downstream MET transducers such as AKT, ERK, PLCγ and STAT3 and a variety of MET-dependent biological endpoints. In all the assays, H1112L was the most sensitive to SU11274, while V1206L was less affected under the used concentration range. The differences in responses to SU11274 are discussed based on a structural model of the MET kinase domain.",

keywords = "Drug resistance, MET, Point mutations, Receptor tyrosine kinases, SU11274",

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AU - Zimmer, Yitzhak

AU - Vaseva, Angelina V.

AU - Medová, Michaela

AU - Streit, Bruno

AU - Blank-Liss, Wieslawa

AU - Greiner, Richard H.

AU - Schiering, Nikolaus

AU - Aebersold, Daniel M.

PY - 2010/3/28

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N2 - Point mutations emerge as one of the rate-limiting steps in tumor response to small molecule inhibitors of protein kinases. Here we characterized the response of the MET mutated variants, V1110I, V1238I, V1206L and H1112L to the small molecule SU11274. Our results reveal a distinct inhibition pattern of the four mutations with IC50 values for autophosphorylation inhibition ranging between 0.15 and 1.5 μM. Differences were further seen on the ability of SU11274 to inhibit phosphorylation of downstream MET transducers such as AKT, ERK, PLCγ and STAT3 and a variety of MET-dependent biological endpoints. In all the assays, H1112L was the most sensitive to SU11274, while V1206L was less affected under the used concentration range. The differences in responses to SU11274 are discussed based on a structural model of the MET kinase domain.

AB - Point mutations emerge as one of the rate-limiting steps in tumor response to small molecule inhibitors of protein kinases. Here we characterized the response of the MET mutated variants, V1110I, V1238I, V1206L and H1112L to the small molecule SU11274. Our results reveal a distinct inhibition pattern of the four mutations with IC50 values for autophosphorylation inhibition ranging between 0.15 and 1.5 μM. Differences were further seen on the ability of SU11274 to inhibit phosphorylation of downstream MET transducers such as AKT, ERK, PLCγ and STAT3 and a variety of MET-dependent biological endpoints. In all the assays, H1112L was the most sensitive to SU11274, while V1206L was less affected under the used concentration range. The differences in responses to SU11274 are discussed based on a structural model of the MET kinase domain.

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Differential inhibition sensitivities of MET mutants to the small molecule inhibitor SU11274

Abstract

Keywords

ASJC Scopus subject areas

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