Although protein-protein interactions possess significant biological importance, identification of small protein-protein interaction modulators (PPIMs) remains challenging due to the flexible nature of proteins. Several fragment-based approaches have been used to identify ligands with good ligand efficiencies, but failure to provide insight into efficient fragment evolution has made the drug discovery process complicated.  Herein, we report the development of a drug discovery approach that generates only biologically active compounds, known as kinetic target-guided synthesis (TGS). A sulfo-click reaction between thio acids and sulfonyl azides was successfully employed for Bcl-XL-and Mcl-1-templated screenings. After obtaining encouraging results, efforts were made to increase the throughput of kinetic TGS by approximately 100-fold. The development, high throughput and use of the new kinetic TGS will be discussed.

Multi-fragment screening of protein-protein interaction modulators via sulfo-click kinetic target-guided synthesis

245th National Meeting (2013)

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