echemi logo
Product
  • Product
  • Supplier
  • Inquiry
    Home > Active Ingredient News > Drugs Articles > The heavy PROTAC technology will subvert the pattern of new drugs, and many listed pharmaceutical companies such as Hengrui and Haisco are actively deploying

    The heavy PROTAC technology will subvert the pattern of new drugs, and many listed pharmaceutical companies such as Hengrui and Haisco are actively deploying

    • Last Update: 2021-04-28
    • Source: Internet
    • Author: User
    Search more information of high quality chemicals, good prices and reliable suppliers, visit www.echemi.com

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;line-height:1.
    5em;box-sizing:border-box ;overflow-wrap:break-word ;'>     

            

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;line-height:1.
    5em;box-sizing:border-box ;overflow-wrap:break-word ;'> In today's era when monoclonal antibodies are not uncommon, four antibodies (the world's first "four antibodies" drug GNC-038) are already available, biotechnology research and development seems to have become the mainstream, and the small molecule drugs of the past seem to be at a low point.
    However, the emergence PROTAC technology, with its subversive imagination of design, unique mechanism of action, challenge "not medicine" target in recent years by many large pharmaceutical companies and the capital sought after, such as Henry, Hai Sike and other
    listed have also Layout of pharmaceutical companies' heavy warehouses .

    In today's era when monoclonal antibodies are not uncommon, four antibodies (the world's first "four antibodies" drug GNC-038) are already available, biotechnology research and development seems to have become the mainstream, and the small molecule drugs of the past seem to be at a low point.
    However, the emergence PROTAC technology, with its subversive imagination of design, unique mechanism of action, challenge "not medicine" target in recent years by many large pharmaceutical companies and the capital sought after, such as Henry, Hai Sike and other
    listed have also Layout of pharmaceutical companies in heavy warehouses .
    In today's era when monoclonal antibodies are not uncommon, four antibodies (the world's first "four antibodies" drug GNC-038) are already available, biotechnology research and development seems to have become the mainstream, and the small molecule drugs of the past seem to be at a low point.
    However, the emergence of PROTAC technology, with its subversive design, unique mechanism of action, and the imaginary space of challenging "unable to drug" targets, has been sought after by many major pharmaceutical companies and capital in recent years, such as Hengrui and Haisco
    .

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>



    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>



    544px;text-align:center;text-indent:0em;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>



    544px;text-align:center;text-indent:0em;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>   1.
    What is 
    PROTAC? 

      1.
    What is 
    PROTAC? 
      1.
    What is 
    PROTAC? 
      1.
    What is 
    PROTAC? 

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>



    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>



    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;line-height:1.
    5em;box-sizing:border-box ;'> What is PROTAC? PROTAC is the abbreviation of PROteolysis TArgeting Chimera, a protein degradation targeted chimera, a bifunctional small molecule, one end is a ligand that binds to the target protein, and the other end is a ligand that binds to the E3 ubiquitin ligase, connected by a chain.
    In the body, the target protein and E3 enzyme can be brought closer, so that the target protein is labeled with ubiquitin, and then degraded through the ubiquitin-proteasome pathway.

    What is PROTAC? PROTAC is the abbreviation of PROteolysis TArgeting Chimera, a protein degradation targeted chimera, a bifunctional small molecule, one end is a ligand that binds to the target protein, and the other end is a ligand that binds to the E3 ubiquitin ligase, connected by a chain.
    In the body, the target protein and E3 enzyme can be brought closer, so that the target protein is labeled with ubiquitin, and then degraded through the ubiquitin-proteasome pathway.

    544px;text-align:center;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;line-height:1.
    5em;box-sizing:border-box ;'> This is a brand-new drug design strategy.
    By designing such triplet small molecule drugs, in theory, any over-expressed and mutated disease-causing proteins can be eliminated to treat diseases.

    This is a brand-new drug design strategy.
    By designing such triplet small molecule drugs, in theory, any over-expressed and mutated disease-causing proteins can be eliminated to treat diseases.



    In simple terms, this process is like the cell handing over the unused files (abnormal protein) to the secretary (E3 enzyme), stamping it with obsolescence (ubiquitination), and throwing it into a paper shredder (proteasome).
    The principle of action of small molecules is to inhibit the production of proteins, while the principle of action of PROTACs is to send these proteins into the proteasome for complete degradation, which breaks the definition of traditional drugs.
    As shown below:
    In simple terms, this process is like the cell handing over the unused files (abnormal protein) to the secretary (E3 enzyme), stamping it with obsolescence (ubiquitination), and throwing it into a paper shredder (proteasome).
    The principle of action of small molecules is to inhibit the production of proteins, while the principle of action of PROTACs is to send these proteins into the proteasome for complete degradation, which breaks the definition of traditional drugs.
    As shown below:

    544px;text-align:center;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>

    544px;text-align:center;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>


    544px;text-align:center;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>


    544px;text-align:center;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>


    544px;text-align:center;text-indent:0em;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>   2.
    Advantages of   PROTAC

      2.
    PROTAC
    advantage  
      2.
    PROTAC
      2.
    PROTAC
    advantage   advantage  

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>





    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>





    ① One of the biggest advantages is to change the target from "undruggable" to "druggable"
    ① One of the biggest advantages is to change the target from "undruggable" to "druggable"
    ② Does not rely on "occupy driver" and has affinity
    ② Does not rely on "occupy driver" and has affinity
    ③ Catalytic protein degradation function
    ③ Catalytic protein degradation function
    ④Overcome drug resistance caused by target protein mutation/overexpression
    ④Overcoming the drug resistance caused by target protein mutation/overexpression Overcoming the drug resistance caused by target protein mutation/overexpression
    ④Does not depend on affinity and can be highly selective
    ④Does not depend on affinity, high selectivity does not depend on affinity, high selectivity

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;line-height:1.
    5em;box-sizing:border-box ;'> ⑤Low toxicity

    ⑤Low toxicity

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>



    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'> Among the disease-related proteins that have been analyzed, up to 80% of the proteins cannot be targeted with existing drugs because they are mostly located in the cell or in the nucleus-macromolecular antibodies cannot get in, and the surface is relatively smooth and not obvious "Pockets"-small molecules can't grasp it firmly.
    Using PROTAC technology, in theory, as long as there are cracks and gaps on the target protein that can be "focused" for a short time.

    Among the disease-related proteins that have been analyzed, up to 80% of the proteins cannot be targeted with existing drugs because they are mostly located in the cell or in the nucleus-macromolecular antibodies cannot get in, and the surface is relatively smooth and not obvious "Pockets"-small molecules can't grasp it firmly.
    Using PROTAC technology, in theory, as long as there are cracks and gaps on the target protein that can be "focused" for a short time.
    Use PROTAC technology, use PROTAC technology,

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>



    Compared with the three major categories of traditional small molecules, monoclonal antibodies, and nucleic acids, PROTAC can be said to be a combination of the best of many people:
    Compared with the three major categories of traditional small molecules, monoclonal antibodies, and nucleic acids, PROTAC can be said to be a combination of the best of many people:

    544px;text-align:center;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>

    544px;text-align:center;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>


    544px;text-align:center;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>


    544px;text-align:center;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>


    544px;text-align:center;text-indent:0em;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>   3.
    Difficulties and challenges of    PROTAC

      3.
     PROTAC difficulties and challenges  
      3.
     PROTAC  PROTAC difficulties and challenges of   the difficulties and challenges  

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>





    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>





    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'> ①Poor drug-making properties of the triplet

    ①The triplet has poor druggability ①The triplet has poor druggability

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>




    Because it is a three-part-like dumbbell-shaped molecule, its water solubility, oral bioavailability, metabolic stability, membrane permeability, synthesis difficulty and cost, PK/PD, etc.
    , are still problems that need to be overcome one by one.
    Because it is a three-part-like dumbbell-shaped molecule, its water solubility, oral bioavailability, metabolic stability, membrane permeability, synthesis difficulty and cost, PK/PD, etc.
    , are still problems that need to be overcome one by one.

    544px;text-align:center;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>

    544px;text-align:center;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>


    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'> ②The problem of off-target toxicity

    ②Off-target toxicity problem ②Off-target toxicity problem

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>




    The degradation of PROTAC targets is more thorough, and even verified targets need to be closely monitored in future clinical trials.
    Another hidden danger is that off-target effects of degradation are difficult to detect and track in preclinical toxicity screening, which increases the risk of later development.
    The degradation of PROTAC targets is more thorough, and even verified targets need to be closely monitored in future clinical trials.
    Another hidden danger is that off-target effects of degradation are difficult to detect and track in preclinical toxicity screening, which increases the risk of later development.

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>



    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'> ③How to effectively form a ternary complex and effectively activate the degradation system

    ③How to effectively form a ternary complex and effectively activate the degradation system ③How to effectively form a ternary complex and effectively activate the degradation system

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>




    PROTAC must form an effective ternary complex with the target protein and E3 enzyme to exert its drug effect.
    How to control the concentration to prevent the drug molecule from forming a binary complex with the target protein and E3 enzyme respectively (hook effect), and the target protein and the E3 enzyme.
    The charge repulsion and three-dimensional structure repulsion in the contact area of ​​E3 enzyme is a big challenge.
    When the ternary complex is formed, whether it can be effectively degraded requires a struggle with deubiquitinating enzymes and target protein re-synthesis until a certain degree of balance is reached.
    PROTAC must form an effective ternary complex with the target protein and E3 enzyme to exert its drug effect.
    How to control the concentration to prevent the drug molecule from forming a binary complex with the target protein and E3 enzyme respectively (hook effect), and the target protein and the E3 enzyme.
    The charge repulsion and three-dimensional structure repulsion in the contact area of ​​E3 enzyme is a big challenge.
    When the ternary complex is formed, whether it can be effectively degraded requires a struggle with deubiquitinating enzymes and target protein re-synthesis until a certain degree of balance is reached.

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>



    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>



    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>



    544px;text-align:center;text-indent:0em;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'>   4.
    Current status of domestic and foreign research and development of PROTAC drugs  

      4.
    Current status of domestic and foreign research and development of
    PROTAC drugs   4.
    Current status   of domestic and foreign research and development of PROTAC drugs   4.
    Current status   of domestic and foreign research and development of PROTAC drugs Current status of domestic and foreign research and development of   PROTAC drugs  

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>



    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>



    544px;text-align:center;text-indent:0em;white-space:normal;background-color:#FFFFFF;box-sizing:border-box ;'> Current status of domestic and foreign research and development of PROTAC drugs

    Current status of domestic and foreign research and development of PROTAC drugs
    Data source: Yaorongyun https://db.
    pharnexcloud.
    com/database/1/table/44?q=PROTAC
    Data source: Yaorongyun https://db.
    pharnexcloud.
    com/database/1/table/44?q=PROTAC

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>


    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'> foreign Arvinas: pioneers PROTAC technology

    foreign Arvinas: pioneers PROTAC technologyforeign Arvinas: pioneers PROTAC technology pioneers PROTAC technology

    544px;text-indent:0em;white-space:normal;background-color:#FFFFFF;text-align:justify;box-sizing:border-box ;'>




    Arvinas was founded in 2013 by Professor Crews, the originator of PROTAC .
    The
    PROTAC drugs in the product pipeline are
    composed of anti-tumor drugs and neurological disease drugs.
    ARV-110 and ARV-471 are currently the company's two fastest-growing PROTAC drugs, and are actively conducting Phase II clinical trials.
    Arvinas was founded in 2013 by Professor Crews, the originator of PROTAC .
    The
    PROTAC
    drugs
    in the product pipeline are composed of anti-tumor drugs and neurological disease drugs.
    ARV-110 and ARV-471 are currently the company's two fastest-growing PROTAC drugs, and are actively conducting Phase II clinical trials.
    PROTAC PROTAC drugs are composed of anti-tumor drugs and neurological disease drugs.
    ARV-110 and ARV-471 are currently the company's two fastest-growing PROTAC drugs, and are actively conducting Phase II clinical trials.
    The drug consists of two parts: anti-tumor drugs and neurological disease drugs.
    ARV-110 and ARV-471 are currently the company's two fastest-growing PROTAC drugs, and are actively conducting Phase II clinical trials.


    About ARV-110:
    About ARV-110: About ARV-110: About ARV-110:



    ARV-110 is Arvinas's world's first oral bioavailable PRAOTC small molecule drug that has entered clinical trials in the field of protein degradation targeted chimeras, and selectively targets the degradation of androgen receptor (AR).
    In May 2019, ARV-110 was approved by the FDA for fast track, mainly used to treat patients with metastatic trend-resistant prostate cancer (mCRPC).
    ARV-110 is Arvinas's world's first oral bioavailable PRAOTC small molecule drug that has entered clinical trials in the field of protein degradation targeted chimeras, and selectively targets the degradation of androgen receptor (AR).
    In May 2019, ARV-110 was approved by the FDA for fast track, mainly used to treat patients with metastatic trend-resistant prostate cancer (mCRPC).
    This article is an English version of an article which is originally in the Chinese language on echemi.com and is provided for information purposes only. This website makes no representation or warranty of any kind, either expressed or implied, as to the accuracy, completeness ownership or reliability of the article or any translations thereof. If you have any concerns or complaints relating to the article, please send an email, providing a detailed description of the concern or complaint, to service@echemi.com. A staff member will contact you within 5 working days. Once verified, infringing content will be removed immediately.

    Contact Us

    The source of this page with content of products and services is from Internet, which doesn't represent Echemi's opinion. If you have any queries, please write to service@echemi.com. It will be replied within 5 days.

    Moreover, if you find any instances of plagiarism from the page, please send email to service@echemi.com with relevant evidence.