CZ415, a Highly Selective mTOR Inhibitor Showing in Vivo Efficacy in a Collagen Induced Arthritis Model

Andrew D. Cansfield; Tammy Ladduwahetty; Mihiro Sunose; Katie Ellard; Rosemary Lynch; Anthea L. Newton; Ann Lewis; Gavin Bennett; Nico Zinn; Douglas W. Thomson; Anne J. Rüger; John T. Feutrill; Oliver Rausch; Alan P. Watt; Giovanna Bergamini

doi:10.1021/acsmedchemlett.6b00149

CZ415, a Highly Selective mTOR Inhibitor Showing in Vivo Efficacy in a Collagen Induced Arthritis Model

Andrew D. Cansfield, Tammy Ladduwahetty, Mihiro Sunose, Katie Ellard, Rosemary Lynch, Anthea L. Newton, Ann Lewis, Gavin Bennett, Nico Zinn, Douglas W. Thomson, Anne J. Rüger, John T. Feutrill, Oliver Rausch, Alan P. Watt, Giovanna Bergamini^*

^*Corresponding author for this work

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

Abstract

CZ415, a potent ATP-competitive mTOR inhibitor with unprecedented selectivity over any other kinase is described. In addition to a comprehensive characterization of its activities in vitro, in vitro ADME, and in vivo pharmacokinetic data are reported. The suitability of this inhibitor for studying in vivo mTOR biology is demonstrated in a mechanistic mouse model monitoring mTOR proximal downstream phosphorylation signaling. Furthermore, the compound reported here is the first ATP-competitive mTOR inhibitor described to show efficacy in a semitherapeutic collagen induced arthritis (CIA) mouse model.

Original language	English
Pages (from-to)	768-773
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	7
Issue number	8
DOIs	https://doi.org/10.1021/acsmedchemlett.6b00149
Publication status	Published - 11 Aug 2016

Keywords

collagen induced arthritis model
inflammation
kinase inhibitor
mTOR

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10.1021/acsmedchemlett.6b00149

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Cansfield, A. D., Ladduwahetty, T., Sunose, M., Ellard, K., Lynch, R., Newton, A. L., Lewis, A., Bennett, G., Zinn, N., Thomson, D. W., Rüger, A. J., Feutrill, J. T., Rausch, O., Watt, A. P., & Bergamini, G. (2016). CZ415, a Highly Selective mTOR Inhibitor Showing in Vivo Efficacy in a Collagen Induced Arthritis Model. ACS Medicinal Chemistry Letters, 7(8), 768-773. https://doi.org/10.1021/acsmedchemlett.6b00149

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title = "CZ415, a Highly Selective mTOR Inhibitor Showing in Vivo Efficacy in a Collagen Induced Arthritis Model",

abstract = "CZ415, a potent ATP-competitive mTOR inhibitor with unprecedented selectivity over any other kinase is described. In addition to a comprehensive characterization of its activities in vitro, in vitro ADME, and in vivo pharmacokinetic data are reported. The suitability of this inhibitor for studying in vivo mTOR biology is demonstrated in a mechanistic mouse model monitoring mTOR proximal downstream phosphorylation signaling. Furthermore, the compound reported here is the first ATP-competitive mTOR inhibitor described to show efficacy in a semitherapeutic collagen induced arthritis (CIA) mouse model.",

keywords = "collagen induced arthritis model, inflammation, kinase inhibitor, mTOR",

author = "Cansfield, {Andrew D.} and Tammy Ladduwahetty and Mihiro Sunose and Katie Ellard and Rosemary Lynch and Newton, {Anthea L.} and Ann Lewis and Gavin Bennett and Nico Zinn and Thomson, {Douglas W.} and R{\"u}ger, {Anne J.} and Feutrill, {John T.} and Oliver Rausch and Watt, {Alan P.} and Giovanna Bergamini",

note = "Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

year = "2016",

month = aug,

day = "11",

doi = "10.1021/acsmedchemlett.6b00149",

language = "English",

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journal = "ACS Medicinal Chemistry Letters",

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Cansfield, AD, Ladduwahetty, T, Sunose, M, Ellard, K, Lynch, R, Newton, AL, Lewis, A, Bennett, G, Zinn, N, Thomson, DW, Rüger, AJ, Feutrill, JT, Rausch, O, Watt, AP & Bergamini, G 2016, 'CZ415, a Highly Selective mTOR Inhibitor Showing in Vivo Efficacy in a Collagen Induced Arthritis Model', ACS Medicinal Chemistry Letters, vol. 7, no. 8, pp. 768-773. https://doi.org/10.1021/acsmedchemlett.6b00149

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T1 - CZ415, a Highly Selective mTOR Inhibitor Showing in Vivo Efficacy in a Collagen Induced Arthritis Model

AU - Cansfield, Andrew D.

AU - Ladduwahetty, Tammy

AU - Sunose, Mihiro

AU - Ellard, Katie

AU - Lynch, Rosemary

AU - Newton, Anthea L.

AU - Lewis, Ann

AU - Bennett, Gavin

AU - Zinn, Nico

AU - Thomson, Douglas W.

AU - Rüger, Anne J.

AU - Feutrill, John T.

AU - Rausch, Oliver

AU - Watt, Alan P.

AU - Bergamini, Giovanna

PY - 2016/8/11

Y1 - 2016/8/11

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KW - collagen induced arthritis model

KW - inflammation

KW - kinase inhibitor

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CZ415, a Highly Selective mTOR Inhibitor Showing in Vivo Efficacy in a Collagen Induced Arthritis Model

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