An overview of PROTACs: a promising drug discovery paradigm

by Selleckchem | May 16 2023

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.

Comments：

PROTACs have several advantages over traditional small-molecule inhibitors, including the ability to target "undruggable" proteins such as transcription factors, scaffolding proteins, and nuclear proteins. Additionally, PROTACs can induce complete degradation of the target protein, rather than just inhibiting its activity, which can result in more robust and long-lasting therapeutic effects.

However, as you mentioned, there are still challenges in designing efficient PROTACs and optimizing their oral bioavailability. One of the key considerations in designing a successful PROTAC is selecting the appropriate target protein, which should have a well-defined ligand-binding pocket and be sufficiently stable for degradation. Additionally, the linker between the two ligands in the PROTAC must be carefully chosen to ensure optimal proximity and orientation for recruitment of the ubiquitin-proteasome system.

There have been several successful examples of PROTACs targeting a range of protein categories, including kinases, transcription factors, and nuclear receptors. Notable clinical trials have demonstrated the efficacy of ARV-110 and ARV-471 in targeting the androgen receptor in prostate cancer, as well as the potential of PROTACs targeting other proteins such as BTK, BRD4, and STAT3.

Overall, PROTAC technology has the potential to revolutionize drug discovery and bring new treatments to patients with currently untreatable diseases. However, further research and development are needed to overcome the challenges and limitations of this approach.