Discovery of a Potent Small Molecule IL-2 Inhibitor through Fragment Assembly

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• 作者：Andrew C. Braisted ; Johan D. Oslob ; Warren L. Delano ; Jennifer Hyde ; Robert S. McDowell ; Nathan Waal ; Chul Yu ; Michelle R. Arkin ; and Brian C. Raimundo
• 刊名：Journal of the American Chemical Society
• 出版年：2003
• 出版时间：April 2, 2003
• 年：2003
• 卷：125
• 期：13
• 页码：3714 - 3715
• 全文大小：72K
• 年卷期：v.125,no.13(April 2, 2003)
• ISSN：1520-5126

文摘

Using a site-directed fragment discovery method called tethering, we have identified a 60 nM small molecule antagonist of a cytokine/receptor interaction (IL-2/IL2R) with cell-based activity. Starting with a low micromolar hit, we employed a combination of tethering, structural biology, and computational analysis to design a focused set of 20 compounds. Eight of these compounds were at least 5-fold more active than the original hit. One of these compounds showed a 50-fold enhancement and represents the highest affinity inhibitor reported against this protein-protein target class. This method of coupling selected fragments with a low micromolar hit shows great potential for generating high-affinity lead compounds.