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

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 computa...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2003-04, Vol.125 (13), p.3714-3715
Main Authors: Braisted, Andrew C, Oslob, Johan D, Delano, Warren L, Hyde, Jennifer, McDowell, Robert S, Waal, Nathan, Yu, Chul, Arkin, Michelle R, Raimundo, Brian C
Format: Article
Language:English
Subjects:
Alkynes - chemistry
Alkynes - pharmacology
Biological and medical sciences
Diverse techniques
Drug Design
Fundamental and applied biological sciences. Psychology
Interleukin-2 - antagonists & inhibitors
Interleukin-2 - chemistry
Interleukin-2 - metabolism
Interleukin-2 Receptor alpha Subunit
Kinetics
Models, Molecular
Molecular and cellular biology
Peptide Fragments - chemistry
Piperidines - chemistry
Piperidines - pharmacology
Protein Conformation
Receptors, Interleukin - agonists
Structure-Activity Relationship
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Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja034247i