September 25, 2022

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The development history of PROTAC over the past 20 years

The development history of PROTAC over the past 20 years


The development history of PROTAC over the past 20 years. 



Targeted protein degradation ( TPD ) is an emerging therapeutic approach that has received much attention because of its therapeutic potential to modulate proteins that are difficult to target with traditional small molecules.

Protein degradation targeting chimera ( PROTAC ) utilizes the natural protein degradation system in cells – ubiquitin protease system ( UPS ) to achieve targeted degradation of target protein ( POI ).

PROTAC is a heterobifunctional small molecule, one end of which targets POI, and the other end recruits E3 ubiquitin ligase to form a ternary complex with a dumbbell-shaped structure.

POI is labeled with ubiquitin, which is then recognized and degraded by proteasome.


In the 20 years since the first report of the molecular concept of PROTACs utilizing the ubiquitin-proteasome system to degrade target proteins, TPD has moved from academia to industry, and many companies have initiated programs for preclinical and early clinical development.

In 2019, the first PROTAC molecules entered clinical trials; in 2020, clinical proof of concept for PROTACs targeting estrogen receptor ( ER ) and androgen receptor ( AR ) cancer targets was demonstrated. With this success, the TPD field is now ready and committed to targets that are considered “untreatable”.



PROTAC overview

The concept of PROTAC was first proposed by Crews et al. in 2001. It can utilize the naturally occurring protein clearance system in the body to reduce protein levels rather than inhibit the function of proteins for the purpose of treating diseases.

Ubiquitin-dependent proteolysis is the main pathway for degrading intracellular proteins and is part of normal cellular maintenance physiology. In this pathway, proteins are degraded by the proteasome in a three-step process, including ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), which coordinate ubiquitin molecules to target proteins ( substrate ) transfer.


The development history of PROTAC over the past 20 years


PROTAC is a heterobifunctional molecule that can be divided into three parts: the first part is connected to the ligand that binds the target protein, the second part is connected to the ligand of E3 ligase, and there is a linker in the middle to connect the first part and the second part. together. Its mechanism of action is very simple, that is, it first links the target protein and E3 ligase together.

After the formation of this ternary complex, ubiquitinase is automatically transferred to the target protein, and then the proteasome targets and degrades the target protein by recognizing the ubiquitinase on the target protein.



Advantages of PROTAC

First, PROTAC molecules have catalytic degradation functions. Unlike each small molecule inhibitor, which can only act on one protein molecule, each PROTAC molecule can degrade many protein molecules, so a very low dose can have a good effect.

And as long as there are a small amount of PROTAC molecules in the cells, the efficacy can be maintained.


Second, the traditional mode of action of small molecules and antibodies requires high concentrations of inhibitors or mAbs to occupy the active site of the target and block the transduction of downstream signaling pathways. The PROTAC does not affect the function of the protein, but mediates the degradation of the target protein.

It does not need to act on the active site of the protein to inhibit its activity, it only needs to have a certain binding rate with the target protein, so there are more target protein binding bodies that can be selected, and it may act on some traditionally undruggable proteins. 


Third, because PROTAC works by degrading the target protein, PROTAC can overcome the problem of drug resistance of such small molecule drugs when the drug resistance of small molecules is caused by the synthesis of more target proteins by cells.

All in all, PROTAC technology combines the advantages of small molecule drugs, macromolecular biopharmaceuticals and RNAi molecules, and may become the key technology for producing the next batch of blockbuster drugs.



Development of PROTAC

The first era of PROTAC began with the pivotal PROTAC paper by Sakamoto et al. in 2001, which was the first in vitro proof-of-concept of PROTAC. Protac-1 was designed to target methionyl aminopeptidase 2 ( METAP2 ), a potent target for inhibiting angiogenesis.

Protac-1 consists of two domains: ovalicin and a 10 amino acid phosphopeptide from nuclear factor-κB inhibitor-α ( NF-κBIα ), which is bound by the E3 ligase β-transducer repeat ( β-TRCP) ) to identify. Protac-1 acts as a link between METAP2 and β-TRCP, enabling the ligase to ubiquitinate METAP2.


The development history of PROTAC over the past 20 years


Subsequently , a peptide derived from hypoxia-inducible factor 1 subunit-α (HIF1α) that binds to vonHippel–Lindau (VHL) E3 ligase was discovered to engineer cell-penetrating PROTACs that degrade a range of POIs.

Technically, these early PROTACs are now considered “biological PROTACs” because they are not complete small-molecule structures, but instead contain peptide ligands for E3 ligases.

However, the discovery of small-molecule mimetics of HIF1α peptides has opened the door for the design of PROTACs entirely based on small-molecule structures.

Since then, molecular development in this area of ​​PROTAC has grown exponentially.


This foundational era of TPD was ended with the first PROTAC drug ARV-110 to enter clinical trials in 2019, which targets the androgen receptor by recruiting it to the CRL4–CRBN ligase complex.

Since then, PROTAC has entered an era of clinical translation, where multiple molecules designed to degrade disease-causing proteins enter the clinic and the field becomes extremely hot.



Clinical Validation of PROTAC

Before PROTAC entered the clinic, many questions still existed.

Will they have drug-like properties? Are they safe in humans? Will they act on the target protein as expected?

Will they be therapeutic? Encouragingly, preliminary positive data from Phase 1 clinical trials of ARV-110 and ARV-471 in 2020 answered all four basic questions in the affirmative.


ARV-110 was evaluated in a Phase I clinical trial (NCT03888612) in patients with multi -treated metastatic castration-resistant prostate cancer ( mCRPC ) .

This trial is an excellent test case for PROTAC, as AR is a well-known driver of prostate cancer and mCRPC patients, especially this refractory subgroup, due to the anti-androgens that are the mainstay of prostate cancer treatment. Therapy is insensitive or resistant, and treatment options are limited. Initial trial data indicated that ARV-110 was well tolerated at doses up to 420 mg.

These data also demonstrate ARV-110-mediated degradation of protein targets in tumors, the first molecular evidence of a PROTAC in humans and showing signs of antitumor activity.

These data support further Phase II clinical trials of ARV-110.


In addition, another ER-targeting PROTAC molecule, ARV-471, entered clinical trials in patients with locally advanced or metastatic breast cancer.

Interim data for ARV-471 demonstrate a manageable tolerability profile and demonstrate a strong clinical efficacy signal, with a 42% clinical benefit rate in a heavily pretreated population and evidence of ER degradation over fulvestrant and other Selective ER degradation of drugs.

Currently, ARV-471 has progressed to Phase II as a single agent in metastatic breast cancer ( NCT04072952 ), and a Phase Ib study evaluating ARV-471 in combination with the CDK4/CDK6 inhibitor palbociclib has also begun.


Early data for both PROTAC molecules demonstrated strong clinical performance, demonstrating their ideal safety profile, potent exposure, and meaningful clinical efficacy in patients, demonstrating the therapeutic viability of this approach.

By the end of 2021, at least 15 targeted PROTAC drugs have entered the clinical stage, and more projects are expected to follow.


The development history of PROTAC over the past 20 years



Development Status of PROTAC


The continuous maturity of PROTAC technology has attracted many companies and capital to enter this field.

First, pioneers and leaders in PROTAC technology have founded companies to develop protein degradation technology.

Companies that have done earlier and better abroad include Arvinas , C4 Therapeutics , Kymera Therapeutics , Vividion , Nurix , Oncopia Therapeutics and so on.


Arvinas, founded by Crews in 2013, is one of the earliest companies to deploy PROTAC. The developed protein degradation technology is mainly used for the treatment of tumors and neurological diseases.

The most advanced ARV-110 and ARV-471 are both in phase II clinical trials for the treatment of prostate cancer and breast cancer, respectively.


C4 Therapeutics, founded in 2015, was founded by James Bradner.

The targets currently deployed are mainly related to tumors, such as IKZF1/3, BRD9, EGFR, BRAF-V600E and RET. The company has C4T TORPEDO, a platform focused on the development of protein degraders, for the design, synthesis and activity evaluation of PROTACs, aiming to discover high-quality protein degraders.

In January 2019, it entered into cooperation agreements with Biogen and Roche for US$415 million and US$900 million respectively.


Kymera Therapeutics, founded in 2016, focuses on the treatment of cancer and immune inflammation with protein degradation technology.

The targets in the layout are IRAK4, STAT3, etc. The most advanced is KT-474, which is currently in Phase I clinical trials. In July 2020, it entered into a multi-planned strategic partnership with Sanofi, receiving an upfront payment of $150 million and potentially more than $2 billion in potential development, regulatory and sales milestones, as well as substantial royalties.


Nurix, founded in 2009, focuses on the development of degraders that can be used for oral administration. The targets of the layout are BTK, CBL-B, etc.

The company has leveraged their deep expertise in E3 ligases and a proprietary DNA-encoded compound library ( DEL ) to build a proprietary drug discovery platform, DELigase, to develop proteolytic drugs or inhibit E3 ligases to increase levels of beneficial proteins.

The company’s fastest-moving protein-degrading drug is NX-2127, currently in Phase I clinical trials for B-cell malignancies that have failed prior therapy.


In addition to the start-up Biotech, pharmaceutical giants such as Novartis, BMS, and Amgen have also joined in overseas companies deploying the PROTAC track. Domestic companies also have a layout, and it is possible to overtake the field of overseas pharmaceutical companies. 



In the past 20 years, PROTAC has been developing rapidly as a cutting-edge technology in drug research and development, especially in the past few years, PROTAC has become a key treatment modality.

Recently, positive results in Phase I and Phase II clinical trials have also allowed us to see the huge therapeutic potential of PROTAC in tumors and other diseases.


PROTAC has a wide range of targets and a huge market. It is believed that with the continuous progress and improvement of this technology, PROTAC can become as successful as small molecule inhibitors, monoclonal antibodies and immunotherapy, so that more patients with diseases can benefit from it. 



1. PROTAC targeted protein degraders: the pastis prologue. Nat Rev Drug Discov. 2022 Jan 18 : 1–20.

The development history of PROTAC over the past 20 years

(source:internet, reference only)

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