RECOBIN-PROTACs · Reversible Covalently Binding PROTACs Technology for Protein Degradation in Cancer Therapy

Reversible Covalently Binding PROTACs Technology for Protein Degradation in Cancer Therapy

Chemical tools to selectively target cancer cells over healthy cells play a vital role in today’s modern medicine. Over the decades, cancer research focuses on the development of small molecules to inhibit the activity of proteins promoting cell proliferation. Acute myeloid leukemia (AML) is an aggressive cancer of the myeloid blood cell lineage and the treatment for AML involves the use of small molecules or monoclonal antibodies that inhibit the activity of proteins promoting leukemia cell proliferation. The drug dose required for efficient inhibition often leads to off-target effects. Cancerous cells can develop resistance to such drugs by developing new mutations in the target protein. In recent years, proteolysis targeting chimeras (PROTACs) technique receives much attention for therapeutic intervention by degradation of disease-causing proteins. The aim of the project was to develop new degradation approaches by incorporating new modalities on PROTACs to address the challenges associated with stabilization of ternary complex formation to reduce the degradation concentration and differentiation of isomers. The reversible covalently binding PROTACs (RECOBIN-PROTACs) consist of a target protein-ligand (JQ1 for BRD4), cereblon E3 ligase ligand (thalidomide), and a chemoselective functional group (benzaldehyde) connected through flexible linkers. The benzaldehyde group of RECOBIN-PROTAC forms a reversible covalent modification with proximal Lys residue (K91/K141) of BET protein BRD4 (near to JQ1 binding pocket) to enable the efficient degradation of BRD4 protein. The building blocks for RECOBIN-PROTAC were synthesized and the final RECOBIN-PROTACs will be explored for demonstration of their therapeutic efficacy in AML cells. Besides, another covalent electrophilic PROTAC method was developed for degradation of the cysteine-containing proteins. The irreversible covalent PROTAC consists of cereblon E3 ligase ligand and chemoselective warhead (benzyloxy pyridinium and carbonylacrylic derivatives) connected through a linker. The ultimate goal of developing these two reversible and irreversible PROTAC approaches is to meet the broad targeting of druggable as well as undruggable proteomes.

Data: CORDIS, © European Union