Diversity-Oriented Synthesis as a Strategy for Fragment Evolution against GSK3β

被引：32

作者：

Wang, Yikai ^{[1
]}

Wach, Jean-Yves ^{[1
]}

Sheehan, Patrick ^{[1
]}

Zhong, Cheng ^{[1
]}

Zhan, Chenyang ^{[4
]}

Harris, Richard ^{[4
]}

Almo, Steven C. ^{[4
]}

Bishop, Joshua ^{[1
,2
,3
]}

Haggarty, Stephen J. ^{[1
,2
,3
]}

Ramek, Alexander ^{[1
]}

Berry, Kayla N. ^{[1
]}

O'Herin, Conor ^{[1
]}

Koehler, Angela N. ^{[1
]}

Hung, Alvin W. ^{[1
,5
]}

Young, Damian W. ^{[1
,6
]}

机构：

[1] Broad Inst Harvard & MIT, Chem Biol Program, 415 Main St, Cambridge, MA 02142 USA

[2] Harvard Med Sch, Dept Neurol & Psychiat, 185 Cambridge St, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, 185 Cambridge St, Boston, MA 02114 USA

[4] Albert Einstein Coll Med, Dept Biochem, 1300 Morris Pk Ave, Bronx, NY 10461 USA

[5] Expt Therapeut Ctr A STAR, 11 Biopolis Way 03-10, Singapore 138667, Singapore

[6] Baylor Coll Med, Ctr Drug Discovery, One Baylor Plaza, Houston, TX 77030 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 09期

关键词：

Diversity oriented synthesis; fragment-based drug discovery; fragment growing GSK3 beta; DRUG DISCOVERY; STRUCTURAL BIOLOGY; NMR-SPECTROSCOPY; SMALL-MOLECULE; CRYSTALLOGRAPHY; PHOSPHORYLATION; INHIBITORS; DESIGN; POTENT;

D O I：

10.1021/acsmedchemlett.6b00230

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3 beta allow the systematic synthesis of related fragment analogues to explore fragment-level structure activity relationship, and finally lead to the synthesis of a more potent compound.

引用

页码：852 / 856

页数：5

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