Abstract

Venetoclax is a drug used to treat several types of cancer in which Bcl-2 is overexpressed. Venetoclax is often prescribed for an extended period of time, and this has led to the emergence of several resistance mutations in both animal models and patients. It has been found that Venetoclax still binds mutant Bcl-2; however, the binding affinity is much weaker compared to wild type Bcl-2. To overcome Venetoclax resistance, we propose an alternative strategy that involves degradation of both wild type and mutant Bcl-2. Herein, we describe efforts towards the design and synthesis of Venetoclax-based small-molecule degraders that recruit Bcl-2 to the ubiquitin proteasome system for targeted degradation.  Notably, we utilized solid phase synthesis, which eliminates the need for tedious purification steps, allowing synthesis to proceed more efficiently.