The BCL-2 family proteins are central regulators of cell death. Anti-apoptotic members (e.g. BCL-2, BCL-XL, MCL-1) contribute to tumor initiation, disease progression and drug resistance. While these proteins represent attractive drug targets for anticancer therapy, antagonism of their function requires disruption of large surface area protein-protein interactions. We have used nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design to develop small molecules that bind with high affinity to multiple anti-apoptotic BCL-2 family proteins including BCL-XL and BCL-2. The 1st-generation dual BCL-2/BCL-XL inhibitor navitoclax exhibited single-agent activity in patients with relapsed or refractory CLL. Platelets, however, are dependent on BCL-XL for survival and as predicted by preclinical data, clinical inhibition of BCL-XL by navitoclax induced a rapid, concentration-dependent and dose-limiting decrease in circulating platelets. Therefore, we re-engineered navitoclax using structure-guided rational design to create the highly potent, orally bioavailable and BCL-2–selective inhibitor venetoclax (ABT-199), which has recently been approved for the treatment of patients with high-risk relapsed-refractory chronic lymphocytic leukemia.
Bio:
Saul Rosenberg is Senior Director of Oncology Discovery at AbbVie. He received his BS degree from MIT and then moved to the University of California at Berkeley where he earned a Ph.D. degree in organic chemistry in the laboratories of Professor Henry Rapoport.
He began his career at Abbott (which became AbbVie in 2013) in the area of Cardiovascular Research where he discovered the renin inhibitor zankiren. He subsequently moved to the Oncology area and currently holds the title of Senior Director. In this capacity, he has overseen the advancement of multiple compounds to the status of clinical candidate, including the Bcl-2 family inhibitors navitoclax and venetoclax and the PARP inhibitor veliparib. He has authored more than 130 publications, is an inventor on 25 U.S. patents and has been invited speak at numerous venues. His current research efforts are focused on the areas of apoptosis, epigenetics and cell cycle regulation.
