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

被引：15

作者：

Cansfield, Andrew D. ^{[1
,3
]}

Ladduwahetty, Tammy ^{[1
,4
]}

Sunose, Mihiro ^{[1
,5
]}

Ellard, Katie ^{[1
,6
]}

Lynch, Rosemary ^{[1
,7
]}

Newton, Anthea L. ^{[1
,8
]}

Lewis, Ann ^{[1
,9
]}

Bennett, Gavin ^{[1
,10
]}

Zinn, Nico ^{[2
]}

Thomson, Douglas W. ^{[2
]}

Rueger, Anne J. ^{[2
]}

Feutrill, John T. ^{[1
,11
]}

Rausch, Oliver ^{[1
,12
]}

Watt, Alan P. ^{[1
,9
]}

Bergamini, Giovanna ^{[2
,13
]}

机构：

[1] Cellzome Ltd, Chesterford Res Pk, Saffron Waldon CB10 1XL, England

[2] Cellzome AG, Meyerhofstr 1, D-69117 Heidelberg, Germany

[3] Heptares Therapeut, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England

[4] Charles River Labs, Early Discovery, Harlow CM19 5TR, Essex, England

[5] Sygnature Discovery Ltd, BioCity, Pennyfoot St, Nottingham NG1 1GF, England

[6] Joyce Frankland Acad, Saffron Walden CB11 3TR, Essex, England

[7] Aqdot Ltd, Iconix Pk,London Rd, Cambridge CB22 3EG, England

[8] LGC Ltd, Newmarket Rd, Fordham CB7 5WW, Cambs, England

[9] Xenovium, Chesterford Res Pk, Saffron Waldon CB10 1XL, England

[10] Bicycle Therapeut Ltd, Babraham Res Campus, Cambridge CB22 3AT, England

[11] SYNth Med Chem, 399 Royal Parade, Parkville, Vic 3052, Australia

[12] Translat Res Partnerships, Natl Inst Hlth Res, 80 London Rd, London SE1 6LH, England

[13] Cellzome GmbH, Meyerhofstr 1, D-69117 Heidelberg, Germany

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 08期

关键词：

mTOR; kinase inhibitor; inflammation; collagen induced arthritis model; COMPETITIVE MAMMALIAN TARGET; KINASE INHIBITORS; CHEMICAL PROBES; T-CELLS; RAPAMYCIN; POTENT; DIFFERENTIATION; PATHWAY; CANCER; VITRO;

D O I：

10.1021/acsmedchemlett.6b00149

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：768 / 773

页数：6

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