$2.4 billion!

On July 22, Pfizer and Arvinas jointly announced an agreement to jointly develop and promote the oral PROTAC protein degrading agent ARV-471 that targets the estrogen receptor (ER) under research
.

The goal of the cooperation is to build ARV-471 as a pillar endocrine therapy for patients with ER-positive breast cancer, covering patients from receiving adjuvant therapy to metastatic breast cancer
.

Arvinas will receive an upfront payment of US$650 million, as well as a milestone payment of up to US$1.
4 billion
.

ARV-471 is used to potentially treat patients with locally advanced or metastatic ER-positive/HER2-negative breast cancer
.

The ER-positive and HER2-negative breast cancer patients recruited in the previously announced phase I clinical trial have received an average of 5 pre-treatment treatments
.

Among the 14 evaluable patients, one patient achieved a confirmed partial remission, with a 51% reduction in tumor lesions
.

In 2022, Arvinas and Pfizer are expected to initiate a number of phase III clinical trials for the treatment of metastatic breast cancer, including the combination with CDK4/6 inhibitors, and launch key research in the treatment of patients with early breast cancer
.

1

       PROTAC mechanism of action

       PROTAC (Proteolysis-targeting chimeras), also known as targeted protein degradation technology, is a new technology that induces targeted protein degradation through the ubiquitin-proteasome system (UPS)
.

       PROTAC is composed of three elements: E3 ubiquitin ligase ligand, target protein ligand and Linker
.

       Targeted protein degradation is currently one of the hot areas in the development of new drugs
.

       2

       Layout of domestic pharmaceutical companies

       The heavy cooperation between Pfizer and Arvinas is expected to detonate the PROTAC boom
.

       Domestic pharmaceutical companies are also actively deploying.
Among them, pioneering pharmaceutical (AR-PROTAC) and Haisco (BTK-PROTAC) are at the forefront of research and development, as follows
.

       Exploit the pharmaceutical industry-GT20029

       Pioneer Pharmaceutical's GT20029 is the world's first topical PROTAC compound to enter the clinical stage.
It was approved by the China Food and Drug Administration in April 2021 to carry out a phase I clinical trial, and it has also entered the clinical stage in the United States
.

       Excessive activation of the androgen receptor pathway is an important link in the pathogenesis of androgenic alopecia and acne
.
GT20029 can effectively block the androgen receptor (AR) signaling pathway and its physiological functions by degrading the androgen receptor protein
.
The effectiveness of GT20029 in preclinical studies is superior to other small molecule AR antagonists.
While producing local curative effects, GT20029 can effectively reduce systemic drug exposure and avoid the side effects of related oral therapeutic drugs
.

       The pioneering pharmaceutical industry began to deploy PROTAC in 2018.
GT20029 is an innovative drug for external use developed based on the PROTAC platform
.

       Haisco——HSK29116

       HSK29116 is a Class 1 innovative chemical drug developed by Haisco.
It is also its first oral BTK-PROTAC small molecule anti-tumor drug to be declared for clinical use
.
It is expected to become a first-in-class drug .

       BTK (Bruton's tyrosine kinase) is a non-receptor tyrosine kinase that plays an important role in the activation, proliferation, survival and differentiation of B cells
.
BTK inhibitors can selectively block BTK kinase activity, interfere with B cell development by regulating signal pathways, and control the progression of various B cell malignant tumors
.
The oral BTK-PROTAC small-molecule anticancer drug HSK29116 developed by Haisco Pharmaceuticals not only has better efficacy on wild-type BTK, but also overcomes the problem of drug-resistant mutations, and is expected to bring more clinical benefits to patients with B-cell malignant tumors.
Benefits and better treatment drugs
.

       At present, the company has launched a phase I clinical trial to evaluate the safety, tolerability and pharmacokinetics/pharmacodynamics of HSK29116 in patients with relapsed or refractory B-cell lymphoma
.

       Ruiyue Bio-CG001419

       Ruiyue Bio is committed to developing first-in-class targeted protein degradation agent drugs for the treatment of cancer and other serious diseases that lack effective therapies
.
CG001419 developed by Ruiyue Biotechnology is a TRK protein degradation agent (neurotrophic factor receptor tyrosine kinase), which is intended to be used for the treatment of cancer and other diseases.
It is expected to submit CG001419 clinical trial applications in China and the United States at the same time
.

       Haichuang Pharmaceutical——HC-X022

       HC-X022 developed by Haichuang Pharmaceutical is a PROTAC molecule designed to inhibit the growth of cancer cells by degrading the full-length androgen receptor and AR splicing mutants
.
At present, it is believed that AR mutations after the failure of existing therapies (androgen receptor inhibitors or androgen synthesis blockers) are the main mechanism for the development of drug resistance in prostate cancer
.
The research and development goal of Haichuang Pharmaceutical is to find a small molecule that can simultaneously degrade full-length AR and splice variants
.
According to information on the official website of Haichuang Pharmaceutical, the PROTAC project is approaching the preclinical candidate compound (PCC) stage
.

       In addition to the above companies, there are also some Chinese biomedical companies that are also developing protein degradation therapies, including Haihe Pharmaceuticals, Lingke Pharmaceuticals, and Meizhi Pharmaceuticals
.

       The emergence of PROTAC has opened up a vast new world for the development of new small molecule drugs
.
The biggest advantage of PROTAC technology is that it can change the target from "non-druggable" to "druggable"
.
Traditional small molecule inhibitors adopt the principle of occupancy-driven regulation, so that 80% of the proteins in human cells cannot find adjustable small molecules
.
However, PROTAC only needs to weakly bind to the target protein to specifically "mark" and "solve" it.
In theory, it can bring new solutions to the current "difficult drug targets"
.

       There are more than 600 kinds of ubiquitin ligase E3 in the human body.
At present, PROTAC technology only uses a few of them.
The huge blue ocean is waiting for the industry to explore
.
PROTAC is a very new technology, and it is because of the short time that this technology has appeared, only a few molecules have entered clinical research at present, which is a brand new track
.
Of course, as an emerging technology, PROTAC also has many problems to be solved urgently
.
For example, PROTAC has a large molecular weight, difficult to form triple complexes, and off-target toxicity
.
However, as people continue to explore PROTAC technology, more and more drugs are expected to move from concept to reality
.

       We expect that on this brand new track, PROTAC molecules will continue to emerge, and more new medicines and good medicines will come out, which will bring the gospel to the majority of patients
.

       refer to:

       1.
Arvinas and Pfizer Announce Global Collaboration to Develop and Commercialize PROTAC? Protein Degrader ARV-471.
Retrieved July 22, 2021, from https://ir.
arvinas.
com/news-releases/news-release-details/arvinas-and -pfizer-announce-global-collaboration-develop-and.

       2.
Clinical Program Update: ARV-471 & ARV-110.
Retrieved December 14, 2020, from https://ir.
arvinas.
com/static-files/ae52b7dd-e872-483a-bd26-070bae7d56b8.

       3.
https://