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

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journal contribution
posted on 11.03.2003 by Andrew C. Braisted, Johan D. Oslob, Warren L. Delano, Jennifer Hyde, Robert S. McDowell, Nathan Waal, Chul Yu, Michelle R. Arkin, Brian C. Raimundo
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/IL2Rα) 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.