The PROTAC technology in drug development

Abstract

Currently, a new technology termed PROTAC, proteolysis targeting chimera, has been developed for inducing the protein degradation by a targeting molecule. This technology takes advantage of a moiety of targeted protein and a moiety of recognizing E3 ubiquitin ligase and produces a hybrid molecule to specifically knock down a targeted protein. During the first decade, three pedigreed groups worked on the development of this technology. To date, this technology has been extended by different groups, aiming to develop new drugs against different diseases including cancers. This review summarizes the contributions of the groups for the development of PROTAC. SIGNIFICANCE OF THE STUDY: This review summarized the development of the PROTAC technology for readers and also presented the author's opinions on the application of the technology in tumor therapy.

Keywords: PROTAC; cancer; drug development; protein degradation; small molecule.

Figure 1

A graph view of the publications on the proteolysis targeting chimera (PROTAC) technology. Research articles and reviews on PROTAC were searched from Pubmed (https://www.ncbi.nlm.nih.gov/pubmed). The literatures were presented chronologically from 2011. Numbers up columns indicate the total number of article and review papers

Figure 2

A diagram to demonstrate the proteolysis targeting chimera (PROTAC) molecule designs. Only effective PROTACs are presented. Targeted protein is labelled in red colour, and the recruited E3 ubiquitin ligase is labelled in blue colour. A box indicate a research group. Abbreviations of the ligands are listed

Figure 3

A schematic diagram of a peptide‐based proteolysis targeting chimera (PROTAC). This PROTAC is composed of a short peptide that binds to E3 ubiquitin ligase and a small molecular that binds to target protein, respectively, followed by polyubiquitination and proteasome degradation of target

Figure 4

A schematic diagram of the small molecule‐based PROTACs. This proteolysis targeting chimera (PROTAC) consists of a ligand on an E3 ubiquitin ligase, a linker, and a ligand on targeted protein

Figure 5

A summary of targeted proteins, ligands for target, ligand for E3 ubiquitin ligases, and recruited E3 ubiquitin ligases. MetAP‐2, methionine aminopeptidase‐2; ER, estrogen receptor; AR, androgen receptor; HTT, huntingtin protein; ERRα, estrogen‐related receptor alpha; AHR, activation of the aryl hydrocarbon receptor; CRABP‐I/II, cellular retinoic acid binding protein‐I/II; BRD4, bromodomain‐containing protein 4; TACC3, transforming acidic coiled‐coil‐3, spindle‐regulatory protein; DHODH, dihydroorotate dehydrogenase; DAPK, death‐associated protein kinase 1; PSD‐95, postsynaptic density protein 95; ALK, anaplastic lymphoma kinase; TBK1, TANK‐binding kinase 1; RIPK2, receptor‐interacting protein kinase 2; c‐Abl, Abelson nonreceptor tyrosine kinase; VHL, von‐Hippel‐Lindau ubiquitin ligase; CMA, chaperon‐meditated autophage; SCFb‐TRCP, Skip‐Cullin‐F box (β‐TRCP) ubiquitin complex; b‐TRCP, b‐transducing repeat‐containing protein; cIAP1, cellular inhibitor of apoptosis protein 1; MDM2, mouse double minute 2 homologue; APC/C, anaphase‐promoting complex/cyclosome