10.1021/ja034247i.s002 Andrew C. Braisted Andrew C. Braisted Johan D. Oslob Johan D. Oslob Warren L. Delano Warren L. Delano Jennifer Hyde Jennifer Hyde Robert S. McDowell Robert S. McDowell Nathan Waal Nathan Waal Chul Yu Chul Yu Michelle R. Arkin Michelle R. Arkin Brian C. Raimundo Brian C. Raimundo Discovery of a Potent Small Molecule IL-2 Inhibitor through Fragment Assembly American Chemical Society 2003 micromolar molecule antagonist method fragment 60 nM IL tethering affinity inhibitor 20 compounds Fragment Assembly 2003-03-11 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Discovery_of_a_Potent_Small_Molecule_IL-2_Inhibitor_through_Fragment_Assembly/3649749 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.