An overview of PROTACs: a promising drug discovery paradigm

Abstract

Proteolysis targeting chimeras (PROTACs) technology has emerged as a novel therapeutic paradigm in recent years. PROTACs are heterobifunctional molecules that degrade target proteins by hijacking the ubiquitin–proteasome system. Currently, about 20–25% of all protein targets are being studied, and most works focus on their enzymatic functions. Unlike small molecules, PROTACs inhibit the whole biological function of the target protein by binding to the target protein and inducing subsequent proteasomal degradation. PROTACs compensate for limitations that transcription factors, nuclear proteins, and other scaffolding proteins are difficult to handle with traditional small-molecule inhibitors. Currently, PROTACs have successfully degraded diverse proteins, such as BTK, BRD4, AR, ER, STAT3, IRAK4, tau, etc. And ARV-110 and ARV-471 exhibited excellent efficacy in clinical II trials. However, what targets are appropriate for PROTAC technology to achieve better benefits than small-molecule inhibitors are not fully understood. And how to rationally design an efficient PROTACs and optimize it to be orally effective poses big challenges for researchers. In this review, we summarize the features of PROTAC technology, analyze the detail of general principles for designing efficient PROTACs, and discuss the typical application of PROTACs targeting different protein categories. In addition, we also introduce the progress of relevant clinical trial results of representative PROTACs and assess the challenges and limitations that PROTACs may face. Collectively, our studies provide references for further application of PROTACs.

PROTACs: A novel strategy for cancer drug discovery and development

“…[19][20][21][22][23][24][25][26][27][28] TPD techniques rely on the ubiquitin-proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates. [29][30][31][32][33][34][35][36][37][38][39][40][41] The concept of PROTAC was first proposed in 2001, and the PROTAC technology has developed rapidly in the past 20 years. 5,8,19,[42][43][44][45] At the present, more than 10 PROTAC degraders have entered clinical Phase I-II trials with ARV-471 and ARV-110 from Arvinas, Inc as the most advanced ones for the treatment of recurrent breast cancer and prostate cancer, respectively.…”

“…TPD has entered its third decade with both opportunities and challenges 19–28 . TPD techniques rely on the ubiquitin–proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates 29–41 …”

Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods

“…However, the mechanistic steps diverge once the degrader reaches the POI. First, TPD is a catalytic process in which a single molecule can cause the degradation of numerous POI copies. , The process commences when the degrader induces proximity between a POI and an E3 ligase by forming ternary complexes . These complexes can involve non-native interactions between the two proteins as the therapeutic strategy often involves repurposing the E3 ligase to act on non-native substrates.…”

SP1 transcriptionally regulates UBE2N expression to promote lung adenocarcinoma progression

“…Ubiquitination is a common post-translational modification and is involved in numerous biological processes, such as cell cycle progression, tumorigenesis, and malignant development [ 4 ]. Ubiquitination is catalyzed by three enzymes: E1-activating enzymes, E2-conjugating enzymes, and E3-ligating enzymes [ 5 , 6 ]. Among these enzymes, E2-conjugating enzymes are important mediators that help in the transfer of ubiquitin to a target lysine side chain [ 7 ].…”