Integrating fragment assembly and biophysical methods in the chemical advancement of small-molecule antagonists of IL-2: An approach for inhibiting protein-protein interactions

被引：68

作者：

Raimundo, BC ^{[1
]}

Oslob, JD ^{[1
]}

Braisted, AC ^{[1
]}

Hyde, J ^{[1
]}

McDowell, RS ^{[1
]}

Randal, M ^{[1
]}

Waal, ND ^{[1
]}

Wilkinson, J ^{[1
]}

Yu, CH ^{[1
]}

Arkin, MR ^{[1
]}

机构：

[1] Sunesis Pharmaceut Inc, San Francisco, CA 94080 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 12期

关键词：

D O I：

10.1021/jm049967u

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Fragment assembly has shown promise for discovering small-molecule antagonists for difficult targets, including protein-protein interactions. Here, we describe a process for identifying a 60 nM inhibitor of the interleukin-2 (IL-2)/IL-2 receptor (IL-2Ralpha) interaction. By use of fragment-based approaches, a compound with millimolar affinity was evolved to a hit series with low micromolar activity, and these compounds were optimized into a lead series with nanomolar affinity. Fragment assembly was useful not only for hit identification, but also for lead optimization. Throughout the discovery process, biophysical methods and structural biology demonstrated that compounds bound reversibly to IL-2 at the IL-2 receptor binding site.

引用

页码：3111 / 3130

页数：20

共 55 条

[1] A new data analysis method to determine binding constants of small molecules to proteins using equilibrium analytical ultracentrifugation with absorption optics [J].