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

BC Raimundo, JD Oslob, AC Braisted…

Index: Braisted, Andrew C.; Oslob, Johan D.; Delano, Warren L.; Hyde, Jennifer; McDowell, Robert S.; Waal, Nathan; Yu, Chul; Arkin, Michelle R.; Raimundo, Brian C. Journal of the American Chemical Society, 2003 , vol. 125, # 13 p. 3714 - 3715

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Citation Number: 83

Abstract

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-2Rα) 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 ...