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When it comes to molecular targeted therapy of tumors, I believe everyone is familiar with it.
This precise treatment has good curative effect and few side effects, which can be said to be a boon for patients with advanced cancer.
However, the currently confirmed driver genes are too limited, making the patient population of targeted therapy relatively limited.
More importantly, non-medicable protein targets (such as KRAS, TP53, etc.
) and inactive mutation sites can be seen everywhere in cancer patients.
The existing small-molecule targeted drugs cannot solve this problem.
Therefore, scientists have been committed to exploring new treatment methods.
In the past two years, a new "targeting strategy" has gradually come into our sight.
01Proteolysis targeting chimeras (PROTAC) is currently a very hot drug development technology.
The structure of PROTAC is very similar to a "dumbbell", which connects the "ligand of the protein of interest" and the "recruiting ligand for E3 ubiquitin ligase" through a "linker".
The ligand of the protein of interest is a potential carcinogenic target protein, and we hope to remove it; E3 ubiquitin ligase acts as a "marker", and the labeled complex can be degraded by the degradation machinery (proteasome) in our body.
PROTAC links the two organically to help remove the target protein (Figure 1).
Figure 1 Schematic diagram of the action of PROTAC Compared with traditional targeted therapy, PROTAC targeted protein technology has many advantages: ▶ It does not need to be tightly bound to the target protein, and only needs to be "labeled" to induce the degradation of the target protein; ▶ Target non-drugable targets (such as KRAS); ▶ can overcome tumor drug resistance; ▶ effectively prolong the action time, and have a long-lasting effect; ▶ can not only affect the enzyme activity of the protein, but also regulate its non-enzymatic activity.
In addition, PROTAC technology has a wealth of potential targets.
A research paper just published in the "Cell" magazine shows that there are 120 potential targets for PROTAC, of which the most commonly degraded proteins are contained in important pathways for tumor proliferation such as the cell cycle (Figure 2) [1].
Figure 2 PROTAC potential targets (A) and 20 protein molecules with the highest degradation frequency (B) 02 has a long history.
The 20-year-old PROTAC technology has finally entered a new stage.
The emergence of a new field is often not sudden, but It is continuously formed on the basis of a large amount of preliminary work.
This is inseparable from the unremitting efforts of scientists.
▶ In 1999, the researchers of Proteinix Company submitted for the first time a patent application for using small molecule compounds to degrade specific proteins based on the ubiquitin mechanism.
▶ In 2001, Professor Craig Crews of Yale University and Dr.
Raymond Deshaies of California Institute of Technology formally proposed the concept of PROTAC.
However, studies have shown that compounds based on these large-molecular-weight peptides are difficult to enter cells to play a role, and the first generation of PROTAC has thus failed.
▶ Scientists have not given up.
In 2008, based on E3's ubiquitin protein ligase MDM2, Professor Crews' team designed the second generation PROTACs that can be used to degrade androgen receptor (AR), and finally made a breakthrough.
▶ In 2013, in order to introduce PROTAC technology into clinical applications, Professor Crews established Arvinas, the world's first drug research and development company using PROTAC technology.
▶ In 2015, the Crews team designed a new generation of PROTAC based on the new E3 ubiquitin ligase VHL and CRBN ligand to reduce the levels of multiple proteins by more than 90%.
In the same year, James Bradner, head of research and development at Novartis, published a new generation of PROTAC molecules based on thalidomide analogues in Science magazine, detonating the entire field.
▶ In 2019, Arvinas AR-targeted oral small molecule PROTAC became the first targeted protein degradation agent to enter clinical trials, becoming another milestone in the field, representing a key step in the direction of PROTAC technology towards a druggable, promising Towards the clinic.
▶ After the establishment of Arvinas, companies such as C4 Therapeutics and Kymera Therapeutics were established one after another, dedicated to exploring the therapeutic potential of small molecule protein degradation agents, and constantly making new contributions in the field of PROTAC technology.
03 Entered the clinic, early human trial data of PROTAC drugs showed anti-tumor activity.
The latest clinical data of two drugs based on PROTAC technology developed by Arvinas, ARV-471 and ARV-110, were announced in December 2020.
The results Appeared anti-tumor activity [2].
▶ ARV-110, an oral protein degrading agent targeting AR, is the world's first PROTAC drug to enter clinical trials.
The drug is currently in Phase I/II clinical trials for patients with metastatic castration-resistant prostate cancer (mCRPC).
The preliminary results of the study showed that ARV-110 can reduce prostate-specific antigen (PSA) levels by more than half (50%) in 40% of patients with AR T878/H875 specific gene mutations.
The drug also showed clinical benefit to resistant patients (Figure 3).
Figure 3 ARV-110 shows initial efficacy in highly drug-resistant patients ▶ ARV-471 is an oral protein degrading agent that targets the estrogen receptor (ER).
ARV-471 has shown strong anti-tumor effect (Figure 4) for a kind of ER+/HER2- advanced breast cancer patients who failed the previous treatment.
It has the potential of "Best-in-class" estrogen receptor degrading agent. Figure 4 Preliminary anti-tumor activity of ARV-471.
At present, Arvinas has started the phase II clinical trial of ARV-110; plans to start the phase II dose expansion trial of ARV-471, and will be used in combination with another targeted drug in the second half of the year.
/3 line therapy for the treatment of metastatic breast cancer.
In addition, many drugs are under development, and the results are worth looking forward to (Figure 5).
Figure 5 Arvinas company research pipeline In addition to Arvinas, other domestic and foreign companies have also made contributions in the PROTAC field.
On January 26 this year, the domestic company Haisco Pharmaceutical Group Co.
, Ltd.
disclosed that its wholly-owned subsidiary Sichuan Haisco Pharmaceutical Co.
, Ltd.
declared that the drug clinical trial application for the innovative drug HSK29116 powder was accepted by the State Drug Administration.
HSK29116 is an oral PROTAC small molecule anti-tumor drug, which can selectively block the activity of BTK kinase and is expected to control the development of various B cell malignant tumors.
Domestic companies such as Lingke Pharmaceutical, Fendi Technology, Suzhou Kaifeng Pharmaceutical, and Wuyuan Biology have also continued to make progress in this field, and many PROTAC drugs are in the hot research and development stage.
04Continuous progress, PROTAC technology redefines small molecule drugs.
The early human test results of the world's first PROTAC drug ARV-110 fired the first shot of PROTAC drugs into the clinic.
Major companies and investment companies at home and abroad continue to join the research and development of PROTAC drugs, and more new PROTAC drugs will go to the clinic in the future.
PROTAC redefines small molecule drugs and opens up a new direction for targeted therapy.
Of course, in terms of clinical practice, PROTAC drugs are still in a relatively early stage.
There are shortcomings such as the slow speed and success rate of developing PROTAC, poor membrane permeability and oral bioavailability, and insufficient human clinical research evidence.
Said that there is still a long way to go. Although there are still many challenges, the preliminary results achieved have already made people place high hopes on PROTAC.
Let us look forward to the latest research results and hope that this new treatment strategy will eventually be used in the clinic to benefit cancer patients.
Reference 1.
Katherine A Donovan, Fleur M Ferguson, Jonathan W Bushman, etal.
Mapping,the.
DegradableKinome Provides,a.
Resource.
for,Expedited,Degrader Development.
Cell.
2020; 183(6): 1714-1731.
e10 .
2.
https://ir.
arvinas.
com/static-files/ae52b7dd-e872-483a-bd26-070bae7d56b8.
This precise treatment has good curative effect and few side effects, which can be said to be a boon for patients with advanced cancer.
However, the currently confirmed driver genes are too limited, making the patient population of targeted therapy relatively limited.
More importantly, non-medicable protein targets (such as KRAS, TP53, etc.
) and inactive mutation sites can be seen everywhere in cancer patients.
The existing small-molecule targeted drugs cannot solve this problem.
Therefore, scientists have been committed to exploring new treatment methods.
In the past two years, a new "targeting strategy" has gradually come into our sight.
01Proteolysis targeting chimeras (PROTAC) is currently a very hot drug development technology.
The structure of PROTAC is very similar to a "dumbbell", which connects the "ligand of the protein of interest" and the "recruiting ligand for E3 ubiquitin ligase" through a "linker".
The ligand of the protein of interest is a potential carcinogenic target protein, and we hope to remove it; E3 ubiquitin ligase acts as a "marker", and the labeled complex can be degraded by the degradation machinery (proteasome) in our body.
PROTAC links the two organically to help remove the target protein (Figure 1).
Figure 1 Schematic diagram of the action of PROTAC Compared with traditional targeted therapy, PROTAC targeted protein technology has many advantages: ▶ It does not need to be tightly bound to the target protein, and only needs to be "labeled" to induce the degradation of the target protein; ▶ Target non-drugable targets (such as KRAS); ▶ can overcome tumor drug resistance; ▶ effectively prolong the action time, and have a long-lasting effect; ▶ can not only affect the enzyme activity of the protein, but also regulate its non-enzymatic activity.
In addition, PROTAC technology has a wealth of potential targets.
A research paper just published in the "Cell" magazine shows that there are 120 potential targets for PROTAC, of which the most commonly degraded proteins are contained in important pathways for tumor proliferation such as the cell cycle (Figure 2) [1].
Figure 2 PROTAC potential targets (A) and 20 protein molecules with the highest degradation frequency (B) 02 has a long history.
The 20-year-old PROTAC technology has finally entered a new stage.
The emergence of a new field is often not sudden, but It is continuously formed on the basis of a large amount of preliminary work.
This is inseparable from the unremitting efforts of scientists.
▶ In 1999, the researchers of Proteinix Company submitted for the first time a patent application for using small molecule compounds to degrade specific proteins based on the ubiquitin mechanism.
▶ In 2001, Professor Craig Crews of Yale University and Dr.
Raymond Deshaies of California Institute of Technology formally proposed the concept of PROTAC.
However, studies have shown that compounds based on these large-molecular-weight peptides are difficult to enter cells to play a role, and the first generation of PROTAC has thus failed.
▶ Scientists have not given up.
In 2008, based on E3's ubiquitin protein ligase MDM2, Professor Crews' team designed the second generation PROTACs that can be used to degrade androgen receptor (AR), and finally made a breakthrough.
▶ In 2013, in order to introduce PROTAC technology into clinical applications, Professor Crews established Arvinas, the world's first drug research and development company using PROTAC technology.
▶ In 2015, the Crews team designed a new generation of PROTAC based on the new E3 ubiquitin ligase VHL and CRBN ligand to reduce the levels of multiple proteins by more than 90%.
In the same year, James Bradner, head of research and development at Novartis, published a new generation of PROTAC molecules based on thalidomide analogues in Science magazine, detonating the entire field.
▶ In 2019, Arvinas AR-targeted oral small molecule PROTAC became the first targeted protein degradation agent to enter clinical trials, becoming another milestone in the field, representing a key step in the direction of PROTAC technology towards a druggable, promising Towards the clinic.
▶ After the establishment of Arvinas, companies such as C4 Therapeutics and Kymera Therapeutics were established one after another, dedicated to exploring the therapeutic potential of small molecule protein degradation agents, and constantly making new contributions in the field of PROTAC technology.
03 Entered the clinic, early human trial data of PROTAC drugs showed anti-tumor activity.
The latest clinical data of two drugs based on PROTAC technology developed by Arvinas, ARV-471 and ARV-110, were announced in December 2020.
The results Appeared anti-tumor activity [2].
▶ ARV-110, an oral protein degrading agent targeting AR, is the world's first PROTAC drug to enter clinical trials.
The drug is currently in Phase I/II clinical trials for patients with metastatic castration-resistant prostate cancer (mCRPC).
The preliminary results of the study showed that ARV-110 can reduce prostate-specific antigen (PSA) levels by more than half (50%) in 40% of patients with AR T878/H875 specific gene mutations.
The drug also showed clinical benefit to resistant patients (Figure 3).
Figure 3 ARV-110 shows initial efficacy in highly drug-resistant patients ▶ ARV-471 is an oral protein degrading agent that targets the estrogen receptor (ER).
ARV-471 has shown strong anti-tumor effect (Figure 4) for a kind of ER+/HER2- advanced breast cancer patients who failed the previous treatment.
It has the potential of "Best-in-class" estrogen receptor degrading agent. Figure 4 Preliminary anti-tumor activity of ARV-471.
At present, Arvinas has started the phase II clinical trial of ARV-110; plans to start the phase II dose expansion trial of ARV-471, and will be used in combination with another targeted drug in the second half of the year.
/3 line therapy for the treatment of metastatic breast cancer.
In addition, many drugs are under development, and the results are worth looking forward to (Figure 5).
Figure 5 Arvinas company research pipeline In addition to Arvinas, other domestic and foreign companies have also made contributions in the PROTAC field.
On January 26 this year, the domestic company Haisco Pharmaceutical Group Co.
, Ltd.
disclosed that its wholly-owned subsidiary Sichuan Haisco Pharmaceutical Co.
, Ltd.
declared that the drug clinical trial application for the innovative drug HSK29116 powder was accepted by the State Drug Administration.
HSK29116 is an oral PROTAC small molecule anti-tumor drug, which can selectively block the activity of BTK kinase and is expected to control the development of various B cell malignant tumors.
Domestic companies such as Lingke Pharmaceutical, Fendi Technology, Suzhou Kaifeng Pharmaceutical, and Wuyuan Biology have also continued to make progress in this field, and many PROTAC drugs are in the hot research and development stage.
04Continuous progress, PROTAC technology redefines small molecule drugs.
The early human test results of the world's first PROTAC drug ARV-110 fired the first shot of PROTAC drugs into the clinic.
Major companies and investment companies at home and abroad continue to join the research and development of PROTAC drugs, and more new PROTAC drugs will go to the clinic in the future.
PROTAC redefines small molecule drugs and opens up a new direction for targeted therapy.
Of course, in terms of clinical practice, PROTAC drugs are still in a relatively early stage.
There are shortcomings such as the slow speed and success rate of developing PROTAC, poor membrane permeability and oral bioavailability, and insufficient human clinical research evidence.
Said that there is still a long way to go. Although there are still many challenges, the preliminary results achieved have already made people place high hopes on PROTAC.
Let us look forward to the latest research results and hope that this new treatment strategy will eventually be used in the clinic to benefit cancer patients.
Reference 1.
Katherine A Donovan, Fleur M Ferguson, Jonathan W Bushman, etal.
Mapping,the.
DegradableKinome Provides,a.
Resource.
for,Expedited,Degrader Development.
Cell.
2020; 183(6): 1714-1731.
e10 .
2.
https://ir.
arvinas.
com/static-files/ae52b7dd-e872-483a-bd26-070bae7d56b8.
