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. 2008 Oct 22;130(42):13820-1.
doi: 10.1021/ja802683u. Epub 2008 Sep 24.

Bcl-XL-templated assembly of its own protein-protein interaction modulator from fragments decorated with thio acids and sulfonyl azides

Xiangdong Hu  1 , Jiazhi Sun, Hong-Gang Wang, Roman Manetsch
Affiliations

Bcl-XL-templated assembly of its own protein-protein interaction modulator from fragments decorated with thio acids and sulfonyl azides

Xiangdong Hu et al. J Am Chem Soc. .

Abstract

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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Figures

Figure 1
Figure 1
Hit identification of acylsulfonamide SZ4TA2 by LC/MS-SIM. (A) Incubation of SZ4 and TA2 in buffer without Bcl-XL. (B) Bcl-XL-templated reaction after 6 hours of incubation. (C) Synthesized SZ4TA2 as reference. (D) Suppression of Bcl-XL-templated reaction by Bak BH3 peptide. (E) Bcl-XL-templated incubation in presence of mutant Bak BH3 peptide. (F) Suppression of Bcl-XL-templated reaction by Bim BH3 peptide. (G) Bcl-XL-templated incubation in presence of mutant Bim BH3 peptide.
Scheme 1
Scheme 1
Bcl-XL-templated assembly of acylsulfonamide SZ4TA2 from fragments decorated with thio acid or sulfonyl azide functionalities.
See this image and copyright information in PMC

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