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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Review Article

Targeted Protein Degradation: An Emerging Therapeutic Strategy in Cancer

Author(s): Samir H. Barghout*

Volume 21, Issue 2, 2021

Published on: 09 April, 2020

Page: [214 - 230] Pages: 17

DOI: 10.2174/1871520620666200410082652

Price: $65

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.

Keywords: PROTAC, hydrophobic tag, molecular glue, targeted protein degradation, thalidomide, fulvestrant, cancer therapy, ubiquitin, proteasome, IMiD.

Graphical Abstract
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