Title:Targeted Protein Degradation: An Emerging Therapeutic Strategy in Cancer
VOLUME: 21 ISSUE: 2
Author(s):Samir H. Barghout*
Affiliation:Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta
Keywords:PROTAC, hydrophobic tag, molecular glue, targeted protein degradation, thalidomide, fulvestrant, cancer therapy, ubiquitin,
proteasome, IMiD.
Abstract:Drug discovery in the scope of cancer therapy has been focused on conventional agents that nonselectively
induce DNA damage or selectively inhibit the activity of key oncogenic molecules without affecting
their protein levels. An emerging therapeutic strategy that garnered attention in recent years is the induction of
Targeted Protein Degradation (TPD) of cellular targets by hijacking the intracellular proteolysis machinery. This
novel approach offers several advantages over conventional inhibitors and introduces a paradigm shift in several
pharmacological aspects of drug therapy. While TPD has been found to be the major mode of action of clinically
approved anticancer agents such as fulvestrant and thalidomide, recent years have witnessed systematic
endeavors to expand the repertoire of proteins amenable to therapeutic ablation by TPD. Such endeavors have
led to three major classes of agents that induce protein degradation, including molecular glues, Proteolysis Targeting
Chimeras (PROTACs) and Hydrophobic Tag (HyT)-based degraders. Here, we briefly highlight agents in
these classes and key advances made in the field with a focus on clinical translation in cancer therapy.
