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.