Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors

被引：19

作者：

Grimster, Neil P. ^{[1
]}

Anderson, Erica ^{[1
]}

Alimzhanov, Marat ^{[1
]}

Bebernitz, Geraldine ^{[1
]}

Bell, Kirsten ^{[1
]}

Chuaqui, Claudio ^{[1
]}

Deegan, Tracy ^{[1
]}

Ferguson, Andrew D. ^{[2
]}

Gero, Thomas ^{[1
]}

Harsch, Andreas ^{[3
]}

Huszar, Dennis ^{[3
]}

Kawatkar, Aarti ^{[1
]}

Kettle, Jason G. ^{[3
]}

Lyne, Paul ^{[1
]}

Read, Jon A. ^{[4
]}

Costa, Caroline Rivard ^{[1
]}

Ruston, Linette ^{[5
]}

Schroeder, Patricia ^{[1
]}

Shi, Jie ^{[1
]}

Su, Qibin ^{[1
]}

Throner, Scott ^{[1
]}

Toader, Dorin ^{[1
]}

Vasbinder, Melissa ^{[1
]}

Woessner, Richard ^{[1
]}

Wang, Haixia ^{[1
]}

Wu, Allan ^{[2
]}

Ye, Minwei ^{[1
]}

Zheng, Weijia ^{[1
]}

Zinda, Michael ^{[1
]}

机构：

[1] AstraZeneca, IMED Biotech Unit, Oncol, Waltham, MA 02451 USA

[2] AstraZeneca, IMED Biotech Unit, Discovery Sci, Waltham, MA 02451 USA

[3] AstraZeneca, IMED Biotech Unit, Oncol, Cambridge CB2 0RE, England

[4] AstraZeneca, IMED Biotech Unit, Discovery Sci, Cambridge CB2 0RE, England

[5] AstraZeneca, IMED Biotech Unit, Pharmaceut Sci, Macclesfield SK10 2NA, Cheshire, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 12期

关键词：

PATENT LITERATURE 2013-2015; AUTOIMMUNE-DISEASES; SIGNAL TRANSDUCER; STAT3; ACTIVATION; FAMILY KINASES; PART; CANCER; IDENTIFICATION; TRANSCRIPTION-3; PROLIFERATION;

D O I：

10.1021/acs.jmedchem.8b00076

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1-3 and TYK2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Herein, we report the discovery of a potent JAK1 inhibitor, 24, which displays, similar to 1000-fold selectivity over the other highly homologous JAK family members (determined by biochemical assays), while also possessing good selectivity over other kinases (determined by panel screening). Moreover, this compound was demonstrated to be orally bioavailable and possesses acceptable pharmacokinetic parameters. In an in vivo study, the compound was observed to dose dependently modulate the phosphorylation of STAT3 (a downstream marker of JAK1 inhibition).

引用

页码：5235 / 5244

页数：10

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