Comprehensive characterization of the Published Kinase Inhibitor Set

被引：236

作者：

Elkins, Jonathan M. ^{[1
]}

Fedele, Vita ^{[1
]}

Szklarz, Marta ^{[1
]}

Azeez, Kamal R. Abdul ^{[1
]}

Salah, Eidarus ^{[1
]}

Mikolajczyk, Jowita ^{[2
]}

Romanov, Sergei ^{[2
]}

Sepetov, Nikolai ^{[2
]}

Huang, Xi-Ping ^{[3
,4
]}

Roth, Bryan L. ^{[3
,4
]}

Zen, Ayman Al Haj ^{[5
]}

Fourches, Denis ^{[6
,15
]}

Muratov, Eugene ^{[6
]}

Tropsha, Alex ^{[6
]}

Morris, Joel ^{[7
]}

Teicher, Beverly A. ^{[7
]}

Kunkel, Mark ^{[7
]}

Polley, Eric ^{[7
]}

Lackey, Karen E. ^{[8
]}

Atkinson, Francis L. ^{[9
]}

Overington, John P. ^{[9
,14
,16
]}

Bamborough, Paul ^{[10
]}

Mueller, Susanne ^{[1
]}

Price, Daniel J. ^{[11
]}

Willson, Timothy M. ^{[11
,14
,18
]}

Drewry, David H. ^{[11
,14
,17
]}

Knapp, Stefan ^{[1
,12
,13
]}

Zuercher, William J. ^{[11
,14
,18
]}

机构：

[1] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium & Target Discovery Inst, Old Rd Campus, Oxford, England

[2] Nanosyn Inc, Santa Clara, CA USA

[3] Univ N Carolina, Sch Med, Natl Inst Mental Hlth Psychoact Act Drug Screenin, NIMH PDSP,Dept Pharmacol, Chapel Hill, NC USA

[4] Univ N Carolina, Sch Med, Div Chem Biol & Med Chem, Chapel Hill, NC USA

[5] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, British Heart Fdn Ctr Res Excellence, Oxford, England

[6] Univ N Carolina, Div Chem Biol & Med Chem, UNC Eshelman Sch Pharm, Lab Mol Modeling, Chapel Hill, NC USA

[7] NCI, Div Canc Treatment & Diag, Rockville, MD USA

[8] Med Univ S Carolina, Charleston, SC 29425 USA

[9] EMBL EBI, Wellcome Trust Genome Campus, Cambridge, England

[10] GlaxoSmithKline, Chem Sci, Stevenage, Herts, England

[11] GlaxoSmithKline, Chem Sci, Res Triangle Pk, NC USA

[12] Goethe Univ Frankfurt, Inst Pharmazeut Chem, Georg Voigt Str 14, Frankfurt, Germany

[13] Buchmann Inst Mol Life Sci BMLS, Frankfurt, Germany

[14] Novartis Vaccines & Diagnost, Holly Springs, NC USA

[15] N Carolina State Univ, Dept Chem, Bioinformat Res Ctr, Box 8204, Raleigh, NC 27695 USA

[16] Stratified Med, London, England

[17] Meryx Pharmaceut, Chapel Hill, NC USA

[18] Univ N Carolina, UNC Eshelman Sch Pharm, SGC UNC, Div Chem Biol & Med Chem, Chapel Hill, NC USA

来源：

NATURE BIOTECHNOLOGY | 2016年 / 34卷 / 01期

基金：

巴西圣保罗研究基金会; 加拿大创新基金会; 英国惠康基金;

关键词：

DRUG DISCOVERY; PROTEIN-KINASE; POTENT INHIBITORS; INTERACTION MAP; IN-VITRO; SELECTIVITY; KINOME; CANCER; ANGIOGENESIS; SCREEN;

D O I：

10.1038/nbt.3374

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.

引用

页码：95 / 103

页数：9

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