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

摘要

Protein-protein interactions are central to many biological processes and hence represent a large and important class of potential targets for human therapeutics. Recent discovery of a variety of low-molecular-weight compounds interfering with protein-protein complexes launches and validates viable routes for a large number of new therapies. However, disrupting or modulating protein-protein interactions with low-molecular-weight compounds remains challenging. Most protein-protein interfaces lack deep pockets that might provide binding sites for small molecules, and they are composed of two relatively large protein surfaces that are complementary with respect to shape and electrostatics. Moreover, the adaptive and flexible nature of amino acid residues on protein surfaces creates additional challenges for lead compound design and discovery.rnThe Bcl-2 family consists of both and- and proapoptotic members, which are central regulators of programmed cell death. The antiapoptotic proteins like Bcl-2, Bcl-X_L, and Mcl-1 het-erodimerize with the proapoptotic constituents, which include the multidomain molecules Bax and Bak, and BH3-only proteins such as Bim, Bad, Bid, Noxa, or Puma, through the conserved BH3 domain. The relative ratios of pro- and antiapoptotic Bcl-2 family proteins determine the ultimate sensitivity or resistance of cells to a wide variety of apoptotic signals. Meanwhile, small molecules have been reported to modulate the extent of heterodimerization between anti- and proapoptotic Bcl-2 family members inducing apoptosis in cancer cells. Using a combination of SAR by NMR screening, parallel synthesis, and structure-guided lead design, Abbott laboratories developed ABT-737 and a large series of analogues displaying inhibition constants in the nanomolar or subnanomolar range.