Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Abstract

Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high-priority goal for cancer therapy. After decades of effort, drug-discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL2 biology, were essential to the development of BH3 mimetics such as the BCL2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL2 biology and facilitated the clinical development of venetoclax.Significance: Basic research into the pathways governing programmed cell death have paved the way for the discovery of apoptosis-inducing agents such as venetoclax, a BCL2-selective inhibitor that was recently approved by the FDA and the European Medicines Agency. Preclinical studies aimed at identifying BCL2-dependent tumor types have translated well into the clinic thus far and will likely continue to inform the clinical development of venetoclax and other BCL2 family inhibitors. Cancer Discov; 7(12); 1376-93. ©2017 AACR.

Figure 1. Apoptotic “priming” and BH3 mimetics

a) BCL-2 family proteins regulate the intrinsic pathway of apoptosis and can be divided into antiapoptotic and proapoptotic subgroups. Antiapoptotic proteins sequester proapoptotic proteins by binding to their BH3 motifs (blue rectangles) and often exhibit preferential binding to specific family members. Some BH3 proteins, such as BIM, can directly activate effector proteins, facilitating their insertion into the mitochondrial outer membrane, oligomerization, and subsequent mitochondrial outer membrane permeabilization (MOMP). b) Antiapoptotic proteins are often overexpressed in cancer cells, where they sequester high levels of proapoptotic proteins to maintain survival. Such cells are poised to initiate apoptosis upon the release of sufficient quantities of proapoptotic proteins, a state referred to as “primed for death”. The figure at left represents a cell with primed BCL-2. Small-molecule BH3 mimetics such as venetoclax (green rectangles) can competitively displace proapoptotic proteins to trigger programmed cell death. However, other antiapoptotic proteins such as BCL-X_L and MCL-1 can capture proapoptotic proteins liberated by venetoclax, thereby acting as resistance factors.

Figure 2. Rational combinations with the BCL-2-selective inhibitor venetoclax

a) A number of chemotherapeutics and targeted agents demonstrate synergistic cancer cell killing when combined with venetoclax, and their mechanisms of action fall into three general categories: 1) agents that trigger elevations in proapoptotic proteins and lead to BCL-2 priming in cancer cells, 2) direct or indirect inhibitors of BCL-X_L or MCL-1 (middle panel), and 3) agents that mobilize tumor cells away from protective niches in lymph nodes and bone marrow (right panel). b) Additional examples of agents that have been shown to synergize with venetoclax and their respective mechanisms of action.