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.

Proteolysis‐targeting chimeras in drug development: A safety perspective

“…At present, cerebion (CRBN) and VHL are the most common E3 ligases utilized in the development of PROTACs although other E3 ligases have been utilized to a lesser extent including MDM2, cIAP1, KEAP1, and RNF114 (Pettersson & Crews, ; Toure & Crews, ; Zou, Ma, & Wang, ). Both pharmaceutical companies and academic labs are seeking to identify new E3 ligases to serve as a platform for PROTAC lead generation.…”

Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery

“…In addition, these targets comprise nuclear receptors, transcriptional regulators and protein kinases, manifesting the universality of PROTACs as anticancer treatments. 35 2.2.4 VHL-based PROTACs. Peptide PROTACs demonstrated the value of the VHL E3 ligase a long time ago.…”

The Impact of Chemical Biology on Drug Discovery

“…Nowadays, chemical biology turned into an integral part of the preclinical drug discovery strategy of most pharmaceutical companies. New technologies like chemoproteomics, CRISPR/Cas and PROTAC platforms have been implemented in industrial drug discovery workflows and are systematically used to validate and modulate potential drug targets. It is to be expected that chemoproteomics will find its place also in clinical development mid‐term …”