Will the PROTAC, which Hengrui is working hard to develop, become the next-generation drug king?

Artificial intelligence + PROTAC, will produce new breakthroughs

Artificial intelligence + PROTAC, will produce new breakthroughs

On October 20, Hengrui Medicine, which had just released its three quarterly report, immediately organized an investor exchange meeting
.

Zhang Lianshan, Deputy General Manager and Global R&D President of Hengrui Pharmaceuticals, vowed in the conference call: We must promote the implementation of research and development results, and truly transform pipeline advantages and technological advantages into product launch and sales advantages
.

In Hengrui’s pipeline, at least the proteolytic targeted chimera (PROTAC), fully human antibody library and high-throughput antibody discovery, antibody conjugated drugs (ADC), T cell engagers, structural biology, etc.
Research on a large platform
.

If any platform can produce drugs, it will be the most cutting-edge breakthrough in the world

If any platform can produce drugs, it will be the most cutting-edge breakthrough in the world

At present, most anti-cancer drugs cannot escape the fate of "dismantling the east wall and replenishing the west wall": either new mutations appear in the lesions, or the patients have drug resistance
.

After all, drugs are not cunning for disease-causing proteins

If the disease-causing protein can be eliminated, humans may completely defeat cancer

May produce the next blockbuster

PROTAC, the full name is protein degradation targeted chimera
.

Many current drugs achieve the purpose of treating diseases by inhibiting disease-causing proteins or increasing immune strength

The purpose of PROTAC technology is to degrade disease-causing proteins

Compared with the current drug development route, the advantages of PROTAC technology are very obvious:

"

First, it can turn "non-drugable" targets into "drugable" targets
.

Human diseases are mostly caused by disease-causing proteins in the body.

First, it can turn "non-drugable" targets into "drugable" targets

Second, the goal is to eliminate oncoproteins and treat the disease from the root cause

Third, it only takes a small amount to be effective, can be used repeatedly, and is highly targeted

"

In December 2020, Arvinas, a pioneer in PROTAC technology, disclosed the results of clinical trials of two related products:

One of the products under development is called ARV-471, which is an oral protein degrading agent
that targets the estrogen receptor (ER) and can be used to treat breast cancer .

According to the results of the first phase of clinical trials, ARV-471 has a clinical benefit rate of 42%, and it is well tolerated and has no adverse reactions of grade 3 or above.

Oral protein degradation agents that target the estrogen receptor (ER) can be used to treat breast cancer

Oral protein degradation agents that target the androgen receptor (AR) can be used to treat metastatic trend-resistant prostates
.
Prostate specific antigen is down-regulated by more than 50%,

After the release of the clinical data, the capital market was also crazy about PROTAC technology, and Arvinas's stock price soared 122% in two trading days
.

Many domestic companies are already developing

Many domestic companies are already developing

PROTAC technology was proposed by Raymond J.
Deshaies of California Institute of Technology and Craig M.
Crews of Yale University in 2001, and it has only been 20 years from theory to practice
.
But its value has been seen by the world, which has attracted the competition of domestic and foreign pharmaceutical companies
.

At the forefront is Arvinas , which was founded by Craig M.
Crews.
Currently, two drugs under research have entered Phase I/II clinical trials
.
After Arvinas, C4 Therapeutics and Kymera Therapeutics also entered the field of protein degradation in 2015 and 2017, respectively
.

At the forefront are Arvinas C4 Therapeutics and Kymera Therapeutics.

These three companies are regarded as the "troika" of PROTAC technology in the industry
.
After the troika, startup companies such as Vividion, Nurix, and Oncopia Therapeutics have also worked in this field
.

In addition, Sanofi, Bojian, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, AstraZeneca and other internationally renowned pharmaceutical companies have also deployed PROTAC through cooperation + self-research
.
Pfizer is the most active
.
On July 22 this year, Pfizer and Arvinas reached a cooperation .
The two parties will jointly develop and promote AVR-471, including upfront payment, milestone payment to equity investment, and the total amount of cooperation is as high as 2.
4 billion US dollars
.

On July 22 this year, Pfizer and Arvinas reached a cooperation agreement between pre-payment, milestone payment and equity investment.
The total amount of cooperation reached US$2.
4 billion
.

In comparison, the progress of domestic companies in the development of PROTAC has been "slow.
" In addition to Hengrui Pharmaceuticals, BeiGene, WuXi AppTec, KaiXin Pharmaceutical, Haisco, Ruiyue Bio, Haichuang Pharmaceutical, Ling Ke Pharmaceutical, Meizhi Pharmaceutical, etc.
have also started related research
.

In contrast, domestic companies have "slowly beaten" the progress of PROTAC development.
Except for Hengrui Pharmaceuticals,

Capital is more active than pharmaceutical companies.
According to data from Arterial.
com, foreign institutions such as Nextech Invest and Third Rock Ventures, and domestic Sequoia Capital, Minhe Capital, Honghui Capital, Tonghe Yucheng, and Kaitai Capital have all participated in the exploration.
Protac technology related company financing
.

According to incomplete statistics, PROTAC has successfully cracked over 100 proteins
.

How far is it from landing?

How far is it from landing?

The market's attention to the prospects of PROTAC technology actually only started in the past five years
.
Therefore, the fastest progress of the current PROTAC products is only in phase I/II clinical trials
.
After all, PROTAC technology still has many problems that have not been solved
.

PROTAC looks like a barbell and consists of three parts: target protein ligand, E3 ubiquitin ligase ligand, and linker
.
Among them, the role of the target protein ligand is to identify the disease-causing protein; the role of the E3 ubiquitin ligase ligand is to label the disease-causing protein as "waste" to promote its elimination; the linker, as the name suggests, is to connect the first two.
And make it fully functional
.

Target protein ligand, E3 ubiquitin ligase ligand, linker
.

An effective PROTAC product requires at least a stable structure
.
The current technology has not yet fully achieved this point
.

An effective PROTAC product requires at least a stable structure
.

Among them, how to find a suitable target protein ligand is a difficult problem
.
At present, the data of pathogenic targets are publicly available, but it is not easy to find suitable ligands that can correspond to these targets;

Secondly, the choice of E3 ubiquitinase ligand is very cautious
.
According to Li Xiang, the head of Bio-Sundia's biological department, there are more than 600 kinds of ubiquitinating enzymes in the
human body , but only 13 kinds of PROTAC technology are actually used .
In this area, still need to continue to explore
.

There are more than 600 kinds of ubiquitinating enzymes, but only 13 kinds of PROTAC technology are actually used
.

Third, the choice of connector is also very important
.
If the connector is too long or too short, it may affect the structural stability and function of the product itself
.

The three have their own circumstances, and when combined, they will test human wisdom even more
.
If it is difficult for humans to find the right one from the vast array of molecules, can AI?

The three have their own circumstances, and when combined, they will test human wisdom even more
.
If it is difficult for humans to find the right one from the vast array of molecules, can AI?

In this regard, foreign companies have begun to practice
.
On August 9 this year, global target discovery AI giant British Silicon Intelligence reached a cooperation with Arvinas, and the two parties will use their respective platforms to jointly develop PROTAC therapy
.

The prerequisite for AI to function is the accumulation of rich data
.
However, the PROTAC field itself has a short history.
Compared with other popular technologies, there are not many entrants, and it does not have an advantage in data algorithms
.

In this way, if PROTAC technology wants to land, there is still a long way to go
.
But it is worth the patience of the market.
After all, root anti-cancer has a future
.

But it is worth the patience of the market.
After all, root anti-cancer has a future
.