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    Home > Active Ingredient News > Antitumor Therapy > Sub-Journal of "Nature": Protein degradation therapy attracts attention. It is expected that at least 15 models will enter...

    Sub-Journal of "Nature": Protein degradation therapy attracts attention. It is expected that at least 15 models will enter...

    • Last Update: 2021-05-03
    • Source: Internet
    • Author: User
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    Although scientists have found that many specific proteins are closely related to human diseases, it is difficult to find small molecules or antibody drugs that can bind to many of these proteins.
    These proteins are also called "non-drugable" targets.
    In the cell, there is a molecule called E3 (ubiquitin) ligase, which can be marked as defective or damaged by attaching a small protein called ubiquitin to the target protein (ubiquitination).
    The labeled protein will eventually be recognized and degraded by the proteasome in the cell.
    Protein degradation agent is a new type of small molecule drug developed based on this mechanism, which selectively degrades disease-causing proteins by regulating E3 ligase.

    Because protein degradation therapy has expanded the range of drug targets, it has become one of the hot technologies that people pay attention to in recent years.
    Recently, the journal Nature Reviews Drug Discovery published an article Targeted protein degraders crowd into the clinic, taking stock of the latest developments in the pipeline of protein degradation therapies, and predicts that by the end of 2021, at least 15 protein degradation therapies under development will enter the clinic.
    Clinical stage.

    PROTAC, the full name Proteolysis Targeting Chimera, is called a protein targeted degradation chimera.
    Its molecule is bispecific and consists of three parts.
    It has a binding ligand at each end, one end can bind to ubiquitin ligase E3, the other end can bind to the target protein (POI, Protein of Interest), and there is a linker in the middle to bind The two linking ligands are connected.
    PROTAC was first proposed in 2001, when Dr.
    Raymond Deshaies of California Institute of Technology and Professor Craig Crews of Yale University described a peptide-based PROTAC in a PNAS paper.
    In 2019, as Arvinas's oral small molecule PROTAC ARV-110 targeting the androgen receptor (AR) became the first protein degrading agent to enter clinical trials, this field has attracted more attention.
    With the deepening of research, the article also summarizes some of the latest trends.

    1.
    Reduce the risk of targets

    1.
    Reduce the risk of targets

    Reducing R&D risks is a key factor in determining project priorities, because it is very difficult to develop drugs on the basis of unclear biological mechanisms.

    Arvinas, founded by Professor Craig Crews in 2013, was one of the first companies to enter the field of protein degradation therapy.
    Androgen receptor (AR) is one of Arvinas's key research targets and has a long research history: flutamide approved in 1989 and enzalutamide approved in 2012 by Astellas have both proven AR antagonism in prostate cancer.
    Clinical effectiveness.
    However, patients usually develop resistance through AR overexpression or amplification.
    In December last year, Arvinas announced the latest clinical results of its PROTAC protein degradation agents ARV-110 and ARV-471.
    ARV-110 is a protein degradation agent targeting AR, and ARV-471 is a protein degradation agent targeting estrogen receptor (ER).
    Both products under development show good potential.
    In the Phase 1/2 clinical trial of ARV-110 in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), among patients with specific gene mutations, 40% of patients reduced prostate-specific antigen (PSA) levels above 50.

    Nurix Therapeutics' research product NX-2127 targets B-cell developmental kinase BTK, which is also a proven target.
    In 2013, Johnson & Johnson's BTK inhibitor ibrutinib was approved for the treatment of various blood cancers.
    As mentioned in the article, NX-2127 continues to make improvements in terms of safety and drug resistance.
    In addition, NX-2127 also provides the possibility of testing two drugs packaged into one protein degrading agent.

    2.
    "First-in-class" drug opportunities

    2.
    "First-in-class" drug opportunities

    Many proteins with catalytically active sites (such as kinases) can also act as scaffold proteins to aggregate protein complexes together, which makes it relatively difficult to develop drugs that target these proteins.
    Protein degradation therapy has advantages in targeting this type of target, providing opportunities for the development of "first-in-class" drugs.
    For example, IRAK4 is a key protein that mediates inflammation caused by the activation of toll-like receptors (TLRs) and IL-1 receptors (IL-1Rs), and it is also one of the most verified pathways in natural immunity.
    In August last year, Kymera Therapeutics announced that it had reached a number of planned strategic cooperation with Sanofi to promote the development and commercialization of the IRAK4 project.
    The goal is to make the IRAK4 project a "first-in-class" protein degradation drug.
    , Used to treat autoinflammatory diseases.

    3.
    Reduce target-related toxicity

    3.
    Reduce target-related toxicity

    On-target toxicity is a key factor that limits the efficacy of drugs, which is particularly prominent in anti-tumor drugs.
    For example, BCL-XL is an anti-apoptotic protein, and navitoclax, jointly developed by Roche and Abbott, has entered phase 2 clinical trials to promote apoptosis activity by inhibiting BCL-XL and BCL-2.
    However, target-related toxicity also kills platelet cells, and the dose of navitoclax must be reduced to limit the toxicity to platelet cells.

    Through the differential selection of E3 ligase, protein degradation therapy is expected to improve this situation.
    There are about 600 E3 ligases in the human proteome, and each enzyme is expressed in a specific cell.
    In a study published in Nature Medicine in 2019, DT2216 showed a better effect than navitoclax in killing cancer cells by linking VHL ligase with navitoclax, and at the same time, it is less toxic to platelets.
    DT2216 is currently in phase 1 clinical trials, and Dialectic is advancing related research.

    4.
    Molecular glue attracts attention

    4.
    Molecular glue attracts attention

    Molecular glue can also successfully induce the degradation of the target protein.
    In simple terms, molecular gel degradation agents are small molecules that can induce a new type of interaction between the E3 ubiquitin ligase substrate receptor and the target protein, leading to the degradation of the target protein.
    Molecular glue has advantages over PROTAC in terms of molecular weight and pharmacological activity.

    The protein degradation therapy CC-92480 developed by Bristol-Myers Squibb is derived from lenalidomide, an approved therapy for the treatment of multiple myeloma (MM).
    One of the mechanism of action of it and its analogue pomalidomide in treating MM is by combining with the E3 ubiquitin ligase called CRBN, causing it to degrade transcription factors such as Ikaros and Aiolos, thereby achieving immunomodulatory and anti-tumor effects.
    effect.
    Based on Nalidomide, the researchers designed CC-92480 with stronger protein degradation ability.
    In the in vitro cell culture test, the stronger the degrading agent's ability to degrade Aiolos transcription factor, the faster it can lead to the death of multiple myeloma cell lines.
    In phase 1 clinical trials, CC-92480 can achieve an objective response rate (ORR) of 54.
    4% in MM patients.

    In addition, in addition to the verified targets (such as IKZF1/3), molecular glues are also being developed to target new targets, such as Helios (IKZF2), GSPT1.
    Helios (IKZF2) is a zinc finger transcription factor that plays an important role in cancer immune signal transduction.
    Novartis developed a molecular gel degradation agent DKY709 as a single agent and combined with PD-1 antibody DR001 to treat advanced solid tumors in a phase 1 clinical trial is underway.
    Bristol-Myers Squibb's innovative protein degradation agent CC-90009 targeting GSPT1 has shown promising anti-leukemia activity in clinical trials.

    Reference materials:

    Reference materials:

    [1] Targeted protein degraders crowd into the clinic.
    Retrieved Mar 22, 2021, from

    [1] Targeted protein degraders crowd into the clinic.
    Retrieved Mar 22, 2021, from
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