Fragment-Derived Selective Inhibitors of Dual-Specificity Kinases DYRK1A and DYRK1B

被引：28

作者：

Walmsley, David Lee ^{[1
]}

Murray, James B. ^{[1
]}

Dokurno, Pawel ^{[1
]}

Massey, Andrew J. ^{[1
]}

Benwell, Karen ^{[1
]}

Fiumana, Andrea ^{[1
]}

Foloppe, Nicolas ^{[1
]}

Ray, Stuart ^{[1
]}

Smith, Julia ^{[1
]}

Surgenor, Allan E. ^{[1
]}

Edmonds, Thomas ^{[2
]}

Demarles, Didier ^{[3
]}

Burbridge, Mike ^{[2
]}

Cruzalegui, Francisco ^{[2
,4
]}

Kotschy, Andras ^{[5
]}

Hubbard, Roderick E. ^{[1
]}

机构：

[1] Vernalis R&D Ltd, Cambridge CB21 6GB, England

[2] Inst Rech Servier, F-78290 Croissy Sur Seine, France

[3] Technol Servier, F-45000 Orleans, France

[4] Evotec France SAS, 195 Route Espagne, F-31036 Toulouse, France

[5] Servier Res Inst Med Chem, H-1031 Budapest, Hungary

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 13期

关键词：

MEDIATES CELL-SURVIVAL; DOWN-SYNDROME; THERAPEUTIC TARGET; CANCER-CELLS; MIRK/DYRK1B; PHOSPHORYLATION; QUIESCENCE; MIRK; G(0); TAU;

D O I：

10.1021/acs.jmedchem.1c00024

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The serine/threonine kinase DYRK1A has been implicated in regulation of a variety of cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, cell differentiation, and metastasis. In addition, elevated-level DYRK1A activity has been associated with increased severity of symptoms in Down's syndrome. A selective inhibitor of DYRK1A could therefore be of therapeutic benefit. We have used fragment and structure-based discovery methods to identify a highly selective, well-tolerated, brain-penetrant DYRK1A inhibitor which showed in vivo activity in a tumor model. The inhibitor provides a useful tool compound for further exploration of the effect of DYRK1A inhibition in models of disease.

引用

页码：8971 / 8991

页数：21

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