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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, 00:00 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.