Selective JAK3 Inhibitors with a Covalent Reversible Binding Mode Targeting a New Induced Fit Binding Pocket

被引：87

作者：

Forster, Michael ^{[1
]}

Chaikuad, Apirat ^{[2
]}

Bauer, Silke M. ^{[1
]}

Holstein, Julia ^{[3
]}

Robers, Matthew B. ^{[4
]}

Corona, Cesear R. ^{[4
]}

Gehringer, Matthias ^{[1
,5
]}

Pfaffenrot, Ellen ^{[1
]}

Ghoreschi, Kamran ^{[3
]}

Knapp, Stefan ^{[2
,6
,7
]}

Laufer, Stefan A. ^{[1
]}

机构：

[1] Eberhard Karls Univ Tuebingen, Dept Pharmaceut Med Chem, Morgenstelle 8, D-72076 Tubingen, Germany

[2] Univ Oxford, Struct Genom Consortium & Target Discovery Inst, Nuffield Dept Clin Med, Old Rd Campus Res Bldg,Roosevelt Dr, Oxford OX3 7DQ, England

[3] Eberhard Karls Univ Tuebingen, Univ Med Ctr, Dept Dermatol, Liebermeisterstr 25, D-72076 Tubingen, Germany

[4] Promega Corp, 2800 Woods Hollow Rd, Madison, WI 53711 USA

[5] Swiss Fed Inst Technol, Inst Pharmaceut Sci, Dept Chem & Appl Biosci, Vladimir Prelog Weg 1-5-10, CH-8093 Zurich, Switzerland

[6] Goethe Univ Frankfurt, Inst Pharmaceut Chem, Max von Laue Str 9, D-60438 Frankfurt, Germany

[7] Buchmann Inst Mol Life Sci, Max von Laue Str 9, D-60438 Frankfurt, Germany

来源：

CELL CHEMICAL BIOLOGY | 2016年 / 23卷 / 11期

基金：

英国惠康基金; 英国工程与自然科学研究理事会; 巴西圣保罗研究基金会; 加拿大创新基金会;

关键词：

KINASE; DISCOVERY; POTENT; PROBES; KINOME;

D O I：

10.1016/j.chembiol.2016.10.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Janus kinases (JAKs) are a family of cytoplasmatic tyrosine kinases that are attractive targets for the development of anti-inflammatory drugs given their roles in cytokine signaling. One question regarding JAKs and their inhibitors that remains under intensive debate is whether JAK inhibitors should be isoform selective. Since JAK3 functions are restricted to immune cells, an isoform-selective inhibitor for JAK3 could be especially valuable to achieve clinically more useful and precise effects. However, the high degree of structural conservation makes isoform-selective targeting a challenging task. Here, we present picomolar inhibitors with unprecedented kinome-wide selectivity for JAK3. Selectivity was achieved by concurrent covalent reversible targeting of a JAK3-specific cysteine residue and a ligand-induced binding pocket. We confirmed that in vitro activity and selectivity translate well into the cellular environment and suggest that our inhibitors are powerful tools to elucidate JAK3-specific functions.

引用

页码：1335 / 1340

页数：6