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Bcl-XL-Templated Assembly of Its Own Protein−Protein Interaction Modulator from Fragments Decorated with Thio Acids and Sulfonyl Azides

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Department of Chemistry, University of South Florida, CHE205, 4202 East Fowler Avenue, Tampa, Florida 33620 and, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612
[email protected]
†University of South Florida.
‡H. Lee Moffitt Cancer Center and Research Institute.
Cite this: J. Am. Chem. Soc. 2008, 130, 42, 13820–13821
Publication Date (Web):September 24, 2008
https://doi.org/10.1021/ja802683u
Copyright © 2008 American Chemical Society
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    Protein−protein interactions have key importance in various biological processes and modulation of particular protein−protein interactions has been shown to have therapeutic effects. However, disrupting or modulating protein−protein interactions with low-molecular-weight compounds is extremely difficult due to the lack of deep binding pockets on protein surfaces. Herein we describe the development of an unprecedented lead synthesis and discovery method that generates only biologically active compounds from a library of reactive fragments. Using the protein Bcl-XL, a central regulator of programmed cell death, we demonstrated that an amidation reaction between thio acids and sulfonyl azides is applicable for Bcl-XL-templated assembly of inhibitory compounds. We have demonstrated for the first time that kinetic target-guided synthesis can be applied not only on enzymatic targets but also for the discovery of small molecules modulating protein−protein interactions.

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    Synthetic procedures, LC/MS-SIM traces, and determination of IC50 values. This material is available free of charge via the Internet at http://pubs.acs.org.

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