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PROTAC Technology: An Effective Targeted Protein Degrader
Poster Title: PROTAC Technology: An Effective Targeted Protein Degrader
Submitted on 07 Jul 2022
Author(s): Sally Zou
Affiliations: Hunan Huateng Pharmaceutical Co. Ltd.
Poster Views: 93
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Poster Information
Abstract: Most of the drugs currently in clinical use are based on small molecules and use an "occupancy-driven" mechanism of action to inhibit the function of proteins so as to treat diseases. Unlike traditional small molecule inhibitors and antagonists, targeted protein degradation (TPD) has been rapidly developed in recent years due to its ability to induce the degradation of disease-causing target proteins, i.e., PROteolysis TArgeting Chimeras (PROTACs), providing a new way of thought for new drug development.

The concept of PROTAC (Proteolysis Targeting Chimeras) was first proposed by Crews et al. in 2001, which is able to lower the protein level instead of inhibiting the function of protein by using the naturally existing protein cleaning system in the body for the purpose of treating diseases.

Figure 1. Protac Structure, source: reference [1]

PROTACs are heterofunctional small molecules consisting of two ligands linked by an appropriate linker: one ligand recruits and binds the protein of interest (POI), while the other recruits and binds the E3 ubiquitin ligase. The mechanism of PROTACs is to use the ubiquitin-proteasome system (UPS) to ubiquitinate and degrade the target protein. Once the PROTAC molecule binds the target protein to the E3 ligase, a ternary complex is formed, which induces the E3 ligase to ubiquitinate the target protein and initiate the degradation process. The ubiquitinated target protein is recognized and degraded by the 26S proteasome, which is part of the UPS eukaryotic cell.

PROTAC vs. Traditional Small-Molecule Drugs: Advantages
(1) Wider range of action, higher activity, and the ability to target undruggable targets
Traditional small molecules and antibodies inhibit the function of target proteins through an "occupancy-driven" pharmacology model, which requires high concentrations of the inhibitor or monoclonal antibody to occupy the active site of the target and block downstream signaling pathways. In contrast, PROTAC is "event-driven", not affecting the function of the protein, but mediating the degradation of the disease-causing target protein. As long as PROTAC mediates the formation of the ternary complex and ubiquitinates target protein, it is theoretically recyclable and therefore can be used repeatedly in catalytic amounts. Moreover, PROTAC can induce the degradation of proteins without active sites, such as scaffold proteins, as long as they can produce binding effects, which can greatly increase the range of targets.

occupancy-driven.pngFigure 2. "occupancy-driven" pharmacology model of tranditional small molecule drugs, source: references [2]
Figure 3. "event-driven" pharmacology model of tranditional small molecule drugs, source: references [2]

According to incomplete statistics, more than 100 proteins have been successfully degraded. These targets include (1) kinase classes, such as RIPK2, BCR-ABL, EGFR, HER2, c-Met, TBK1, CDK2/4/6/9, ALK, Akt, CK2, ERK1/2, FLT3, PI3K, BTK, Fak, etc.; (2) BET proteins, such as BRD2/4/6/9; (3) nuclear receptors, such as AR, ER, etc. (4) other proteins, such as MetAp-2, Bcl-xL, Sirt2, HDAC6, Pirin, SMAD3, ARNT, PCAF/GCN5, Tau, FRS2, etc. These include " undruggable targets", such as the transcription factor regulatory protein pirin and the epigenetic-related protein PCAF/GCN5. In addition, according to a Nature report in Janurary, at least 21 protein degraders (including PROTAC and molecular glue) are in clinical trials.

When it comes to undruggable targets, it is imperative to mention RAS (KRAS, HRAS and NRAS). As the most common mutated gene in cancer, RAS is an important driver of lung, colorectal and pancreatic cancers. For more than 40 years of discovery and research, there have been no drugs available for this target. Finally, in May 2021, Amgen's KRAS-G12C irreversible inhibitor AMG510 (Sotorasib) was successfully launched, putting an end to the "undruggability" of this target. For KRAS-G12C mutation, Crews et al. designed and synthesized PROTAC based on KRAS inhibitors AMG510 and MRTX849, and the activity assay identified degraders with good degradation activity, which may provide a new solution for further overcoming RAS. It is foreseeable that not only G12C may be overcome by PROTAC technology, but also for other mutations.
Summary: PROTACs are heterofunctional small molecules consisting of two ligands linked by an appropriate linker: one ligand recruits and binds the protein of interest (POI), while the other recruits and binds the E3 ubiquitin ligase. References: [1] Zhao HY, Yang XY, Lei H, et al. Discovery of potent small molecule PROTACs targeting mutant EGFR. Eur J Med Chem. 2020;208:112781. doi:10.1016/j.ejmech.2020.112781
[2] Salami J, Crews CM. Waste disposal-An attractive strategy for cancer therapy. Science. 2017;355(6330):1163-1167. doi:10.1126/science.aam7340
[3] Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs, Michael J. Bond, Ling Chu, Dhanusha A. Nalawansha, Ke Li, and Craig M. Crews, ACS Central Science 2020 6 (8), 1367-1375, DOI: 10.1021/acscentsci.0c00411
[4] Bondeson DP, Smith BE, Burslem GM, et al. Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead. Cell Chem Biol. 2018;25(1):78-87.e5. doi:10.1016/j.chembiol.2017.09.010
[5] Huang, Hai-Tsang et al. “A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader.” Cell chemical biology vol. 25,1 (2018): 88-99.e6. doi:10.1016/j.chembiol.2017.10.005
[6] Qin C, Hu Y, Zhou B, et al. Discove
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