Selecting efficacious Bcl-2 family inhibitors for optimal clinical outcome

Despite several decades of extensive research focus in the development of small molecule inhibitors that target the pro-survival BH-3 family members especially Bcl-2, a clinically successful agent is yet to emerge. The majority of agents either show poor target engagement in humans or their use is limited by acute toxicity, especially thrombocytopenia. In the recent paper in Science Translational Medicine, Leverson and colleagues investigate a novel combination of Bcl-2 family inhibitors that is predicted to present a less toxic yet highly selective way of targeting the Bcl-2 pathway (1).