The Discovery of Navitoclax, a Bcl-2 Family Inhibitor

A case history of the Abbott Oncology Bcl-2/Bcl-xL inhibitors program is presented. The target proteins interact with other members of the Bcl family through surfaces that are very large and hydrophobic even compared to other PPIs that have been targeted by pharma. Resulting inhibitors are correspondingly large and hydrophobic and thus tend to be highly protein bound and possess low oral bioavailability. The Abbott drug discovery effort began with the creation of a soluble, stable version of Bcl-xL, and a solution structure of Bcl-xL bound to a native ligand. Structural support facilitated efforts to find chemical matter, which was accomplished through fragment screening. Structure-based drug design was also employed throughout the project, with the discovery process characterized by separate optimization of two widely separated hydrophobic hot spots. ABT-737, an IV-only compound, was initially selected as a development candidate. Later, efforts to derive an orally bioavailable compound from the same chemical series produced navitoclax (ABT-263), an extremely potent Bcl-2/Bcl-xL inhibitor, currently in Phase II clinical trials for cancer.