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    Home > Medical News > Medical World News > Nature: After PROTAC, another protein degradation agent is coming...

    Nature: After PROTAC, another protein degradation agent is coming...

    • Last Update: 2021-01-18
    • Source: Internet
    • Author: User
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    the | The protein degradation induced by man-called small molecules has become a powerful treatment strategy, and the clinical efficacy of thalidamine-type drugs in treating blood malignancies has been confirmed.
    such anti-cancer drugs as represented by nadamine and pomadamine can redirect the E3 ubiganic connective enzyme CRL4CRBN, thereby causing transcription factors IKZF1 and IKZF3 polysulphation, resulting in the degradation of IKZF1 and IKZF3 by proteases.
    this induced new interaction between the E3 ubibin connecting enzyme substrates and the target protein, resulting in the degradation of the target protein of small molecules called molecular gel degradation agents.
    in addition to molecular gel degradation agents, other small molecules, such as the recently popular PROTACs, have also been developed to degrade a wide range of clinically relevant targets, including kinases, nucleopres and apparent genetic enzymes.
    the mechanism of the molecular adhesive degradation agent, one end of the PROTACs molecule binds to the target protein and the other end binds to the E3 ubigan connective enzyme.
    and E3 Ubibusin connective enzyme can mark a small protein called ubibin as defective or damaged by attaching it to the target protein.
    , the cell's protein crusher (i.e., the 26S protease) identifies and degrades the labeled target protein.
    , however, while protein degradation agents such as molecular glues and PROTACs have shown sustained degradation and significant effects on target proteins, there are some proteins that are not suitable for the degradation mechanisms available.
    example is BCL6.
    PROTACs targeting BCL6 showed that BCL6 could not be degraded sufficiently to induce cancer cell growth inhibition.
    BCL6, known as B celll ymphoma 6, is a promising drug target for the treatment of non-Hodgkin's lymphoma, which includes diffuse large B-cell lymphoma and fable lymphoma.
    increase in BCL6 expression caused by soosome cell BCL6 contouring, exon mutation, initiator mutation or regulatory path mutation are common drivers of B cell malignant tumors.
    in genetically engineered mice, BCL6 over-expression was sufficient to drive the development of lymphoma.
    BCL6 as the main transcription inhibitor, can inhibit a series of genes related to DNA damage response, cell cycle checkpoints and differentiation.
    BCL6 from lymphoma cells can cause tumor development to stall.
    some peptides and small molecule inhibitors targeted at BCL6 have shown efficacy in the body, they are only effective at high concentrations, which limits their conversion to clinically treated drugs.
    : In a new study published in Nature on November 18, a team of scientists from the Broad Institute and the Dana-Farber Cancer Institute in the United States reported on a small molecule that targets the degradation of BCL6, BI-3802, through a new degradation mechanism.
    studies have shown that BI-3802 treatment induces rapid ubibination and degradation of BCL6, leading to significant desuppression of BCL6 and anti-proliferation of diffuse large B-cell lymphoma cell line.
    , BI-3802 induces higher pharmacological activity than BCL6 inhibitors such as BI-3812 and PROTACs that target BCL6.
    BI-3802 is a small molecule that binds to the BCL6 BTB domain (Broad-complex, Tramtrack and Bric-brac domain).
    by observing the behavior of recombinant BCL6 in-body, the study found that in the absence of BI-3802, BCL6 exists in the form of monodisperse particles.
    , however, during the presence of BI-3802, scientists observed the formation of a sine structure with rules (figure b below).
    freezing electroscope studies have shown that BI-3802 induces the polymerization of BCL6.
    BI-3802 in vitro induced the formation of the BCL6 helix filament structure (source: Nature) using two complementary genome-scale CRISPR-Cas9 gene screening to analyze the mechanism of BI-3802 induced BCL6 degradation found that non-cullin (non-cull-cullin) E3 ubiganic connection enzyme SIAH1 played a key role in it.
    knowledge card: Cullin-RING ligases (CRLs) the largest family of Ubigan connective enzymes has formed more than 250 CRLs by assembling substrate receptors and adapter proteins around different cullin skeletons.
    to investigate how BI-3802-induced BCL6 polymerization affects SIAH1-mediated degradation, researchers tested SIAH1 recruitment and BCL6 ubibinization in introphy and cells.
    results show that BI-3802-induced polymerization enhances the interaction between BCL6 and SIAH1 (SIAH1 and BI-3802-induced polymerization of BCL6 significantly increased affinity), resulting in BCL6 ubibinization and degradation acceleration.
    BCL6 aggregation enhances interaction with SIAH1 and ubiquitinization (source: Nature) concludes that, combining functional screening, bio-chemical analysis, and structural profiles, they confirm that the combination of bi-3802 and BCL6's BTB domain triggers higher-order BCL6 assembly.
    this polymerization process promotes BCL6 ubibinization and protease degradation mediated by the E3 connective enzyme SIAH1.
    SIAH1 identifies the VxP base sequence at the far end of the BCL6 drug binding point.
    That is, the BI-3802 treatment led to the formation of intracellular foci containing BCL6 and SIAH1, representing a new targeted protein degradation mechanism, in which small molecule drugs insulation the target protein by inducing polymerization and subsequent degradation.
    findings set the direction for the development of new protein degradation agents.
    reference: 1 siko-aj S'abicki et al. Small-molecule-induced polymerization triggers degradation of BCL6. Nature(2020).
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