Chapter 15:Targeting Protein–Protein Interactions: Dual Inhibitors of Bcl-2 and Bcl-xL

The discovery of dual inhibitors of anti-apoptotic proteins Bcl-2 and Bcl-xL is described. Bcl-xL and Bcl-2 act through protein–protein interactions with other members of the Bcl family, creating specific obstacles deriving from the nature of these targets – high protein binding, hydrophobicity, and low oral bioavailability. Access to soluble, stable versions of the target proteins allowed structural biology support that was crucial to this effort. Solving this problem with respect to Bcl-xL, and later Bcl-2, followed by parallel assay development allowed understanding of similarities and differences in the two target proteins. Fragment screening was used to navigate the early stage of the project, while structure-based drug design was employed throughout. Early compounds were somewhat Bcl-xL selective, while later compounds much more potent against both targets, particularly Bcl-2, leading to robust potentiation of standard chemotherapeutics and single agent activity in a variety of hematological cancers. ABT-737, a large, hydrophobic compound, was initially selected as a development candidate. Later, efforts to derive an orally bioavailable compound from the same chemical series culminated in the discovery of ABT-263, a rationally designed Bcl-2/Bcl-xL inhibitor, which is currently in phase II clinical trials for cancer.