Figure 5.

Schematic illustration of the SAR by NMR approach as applied to Bcl-xL and Bcl-2. (1) Starting from the ¹⁵N-labeled target, a pair of fragments were identified that bound to adjacent regions of the protein surface. (2) The three-dimensional structure of the ternary complex (PDB ID 1YSG) with these two small fragments was used to guide (3) the design of bidentate compounds, resulting in the first clinical candidate (4) ABT-737. Additional structural studies with optimized bidentate compounds led to the design of a further clinical candidate, ABT-199, with improved pharmacological properties and selectivity for Bcl-2.