PROTAC’ing oncoproteins: targeted protein degradation for cancer therapy

Abstract

Molecularly targeted cancer therapies substantially improve patient outcomes, although the durability of their effectiveness can be limited. Resistance to these therapies is often related to adaptive changes in the target oncoprotein which reduce binding affinity. The arsenal of targeted cancer therapies, moreover, lacks coverage of several notorious oncoproteins with challenging features for inhibitor development. Degraders are a relatively new therapeutic modality which deplete the target protein by hijacking the cellular protein destruction machinery. Degraders offer several advantages for cancer therapy including resiliency to acquired mutations in the target protein, enhanced selectivity, lower dosing requirements, and the potential to abrogate oncogenic transcription factors and scaffolding proteins. Herein, we review the development of proteolysis targeting chimeras (PROTACs) for selected cancer therapy targets and their reported biological activities. The medicinal chemistry of PROTAC design has been a challenging area of active research, but the recent advances in the field will usher in an era of rational degrader design.

PROTAC EZH2 degrader-1 overcomes the resistance of podophyllotoxin derivatives in refractory small cell lung cancer with leptomeningeal metastasis

“…Recently, PROTACs [ 22 ] have been developed for inhibiting EZH2 [ 37 , 54 , 55 ]. PROTACs are advantageous due to their high activity, low toxicity, broad target specificity, and ability to overcome challenges posed by target gene mutations [ 56 ]. After binding to the ligand, PROTACs enter the tumour cell, bind specifically to one end of the EZH2 protein, and recruit ubiquitin E3 ligase at the other end to form a triplet EZH2-PROTAC-E3 ligase complex [ 22 ].…”

Small Molecule Drugs Targeting Viral Polymerases

“…While PROTAC technology has been primarily exploited within the anticancer field [195][196][197], its application in the antiviral area is gaining attention [198][199][200][201]. Specifically, PROTAC compounds may be potentially developed against a broad range of viruses by customizing the recruiting ligands to different viral polymerases.…”

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

“…PROTACs consist of three key components: a target protein ligand, a E3 ubiquitin ligand, and a linker. Target protein ligand is the part of the PROTAC molecule that specifically binds to the protein targeted for degradation ( 60 ). The selection of this ligand is critical as it ensures the specificity of the PROTAC for its intended protein target ( 61 ).…”