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

共 28 条

[1] Ligand efficiency indices for effective drug discovery
Abad-Zapatero, Cele
[J]. EXPERT OPINION ON DRUG DISCOVERY, 2007, 2 (04) : 469 - 488
[2] Phosphatidylinositol 3-Kinase (PI3K) and Phosphatidylinositol 3-Kinase-Related Kinase (PIKK) Inhibitors: Importance of the Morpholine Ring
Andrs, Martin
Korabecny, Jan
Jun, Daniel
Hodny, Zdenek
Bartek, Jiri
Kuca, Kamil
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (01) : 41 - 71
[3] The promise and peril of chemical probes
Arrowsmith, Cheryl H.
Audia, James E.
Austin, Christopher
Baell, Jonathan
Bennett, Jonathan
Blagg, Julian
Bountra, Chas
Brennan, Paul E.
Brown, Peter J.
Bunnage, Mark E.
Buser-Doepner, Carolyn
Campbell, Robert M.
Carter, Adrian J.
Cohen, Philip
Copeland, Robert A.
Cravatt, Ben
Dahlin, Jayme L.
Dhanak, Dashyant
Edwards, Aled M.
Frye, Stephen V.
Gray, Nathanael
Grimshaw, Charles E.
Hepworth, David
Howe, Trevor
Huber, Kilian V. M.
Jin, Jian
Knapp, Stefan
Kotz, Joanne D.
Kruger, Ryan G.
Lowe, Derek
Mader, Mary M.
Marsden, Brian
Mueller-Fahrnow, Anke
Mueller, Susanne
O'Hagan, Ronan C.
Overington, John P.
Owen, Dafydd R.
Rosenberg, Saul H.
Roth, Brian
Ross, Ruth
Schapira, Matthieu
Schreiber, Stuart L.
Shoichet, Brian
Sundstrom, Michael
Superti-Furga, Giulio
Taunton, Jack
Toledo-Sherman, Leticia
Walpole, Chris
Walters, Michael A.
Willson, Timothy M.
[J]. NATURE CHEMICAL BIOLOGY, 2015, 11 (08) : 536 - 541
[4] Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors
Bantscheff, Marcus
Eberhard, Dirk
Abraham, Yann
Bastuck, Sonja
Boesche, Markus
Hobson, Scott
Mathieson, Toby
Perrin, Jessica
Raida, Manfred
Rau, Christina
Reader, Valerie
Sweetman, Gavain
Bauer, Andreas
Bouwmeester, Tewis
Hopf, Carsten
Kruse, Ulrich
Neubauer, Gitte
Ramsden, Nigel
Rick, Jens
Kuster, Bernhard
Drewes, Gerard
[J]. NATURE BIOTECHNOLOGY, 2007, 25 (09) : 1035 - 1044
[5] Rapamycin passes the torch: a new generation of mTOR inhibitors
Benjamin, Don
Colombi, Marco
Moroni, Christoph
Hall, Michael N.
[J]. NATURE REVIEWS DRUG DISCOVERY, 2011, 10 (11) : 868 - 880
[6] Bergamini G, 2012, NAT CHEM BIOL, V8, P576, DOI [10.1038/nchembio.957, 10.1038/NCHEMBIO.957]
[7] Know your target, know your molecule
Bunnage, Mark E.
Gilbert, Adam M.
Jones, Lyn H.
Hett, Erik C.
[J]. NATURE CHEMICAL BIOLOGY, 2015, 11 (06) : 368 - 372
[8] Target validation using chemical probes
Bunnage, Mark E.
Chekler, Eugene L. Piatnitski
Jones, Lyn H.
[J]. NATURE CHEMICAL BIOLOGY, 2013, 9 (04) : 195 - 199
[9] EFFECTS OF ORALLY-ADMINISTERED RAPAMYCIN IN ANIMAL-MODELS OF ARTHRITIS AND OTHER AUTOIMMUNE-DISEASES
CARLSON, RP
BAEDER, WL
CACCESE, RG
WARNER, LM
SEHGAL, SN
[J]. ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, 1993, 685 : 86 - 113
[10] Mammalian Target of Rapamycin Signaling Is Crucial for Joint Destruction in Experimental Arthritis and Is Activated in Osteoclasts From Patients With Rheumatoid Arthritis
Cejka, Daniel
Hayer, Silvia
Niederreiter, Birgit
Sieghart, Wolfgang
Fuereder, Thorsten
Zwerina, Jochen
Schett, Georg
[J]. ARTHRITIS AND RHEUMATISM, 2010, 62 (08): : 2294 - 2302

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