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    Home > Medical News > Medical World News > Latest review of protac: focusing on cancer prevention

    Latest review of protac: focusing on cancer prevention

    • Last Update: 2020-06-19
    • Source: Internet
    • Author: User
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    The full name of protacs is proteolysis targeting chimeras, i.eproteolysis targeting chimerasIts structure looks like dumbbells, connecting "ligands of interest proteins" and "recruitment ligands of E3 ubiquitin ligases" through a "linker"In other words, one end of protacs binds to the interest protein (i.etarget protein) and the other end binds to E3 ubiquitin ligaseE3 ubiquitin ligase can be labeled as defective or damaged protein by attaching a small protein called ubiquitin to the target proteinAfter that, the cell's protein Shredder (i.e., proteasome) processes the tagged target protein< br / > with the disclosure of positive phase I clinical data of arv-110, the world's first small molecule protein degradation agent developed based on protacs, the heat in this field has further increased, and many pharmaceutical and biotechnology companies have deployed this technologyAlthough it has the potential to treat many diseases, at present, protocs are mainly investigated for their potential to treat cancer< br / > < br / > < br / > on May 31, a team of scientists from the University of Florida in the United States published a review in nature's oncogene magazine, focusing on a new anticancer therapy based on protacs [1]< br / > the authors point out that the use of protacs to degrade proteins that are essential for tumorigenesis has become a potential cancer treatment strategySince its first discovery in 2001, protocs technology has been developed to target a variety of cancer targetsIn this paper, they discussed the potential and safety of protocs as anticancer therapies, with particular attention to the development of tumor specific / selective protocsFigure 1 of < br / > < br / > < br / / > article explains the mechanism of Protecs mediated protein degradation, which is divided into three typesFigure a is a schematic diagram of the general mechanism of protac induced degradation of proteins of interestAs mentioned above, PROTAC molecules recruit E3 ubiquitin ligase to the protein of interest, which makes the protein of interest labeled by a large number of ubiquitin moleculesAfter that, the polyubiquitinated protein of interest will be recognized by proteasome and then degradedAfter that, protoc molecules will be recycled to induce the next round of degradation< br / > figure B explains the mechanism of the self degradation of E3 ligase mediated by Homo protacsOne Homo protac recruits an E3 ligase molecule (such as crbn or VHL) to another E3 ligase molecule, and then two-way polyubiquitination of E3 ligase molecule occurs, and then both molecules are degraded by proteasome< br / > figure C explains the mechanism of photo protocs mediated degradation of interest proteinsIn photo protac, a photomovable group is attached to an interest ligand or E3 ligase ligand or linkerAfter external light irradiation, the light movable group was separated from photo-PROTAC and converted into active PROTAC for protein degradationThe research field of < br / > < br / > < br / > protacs is relatively new, but develops rapidlyFigure 2 summarizes some important developments since the technology was first discovered in 2001If the first small molecule protac was reported in 2008, it is an important turning point in the development of this field [3]; then, in 2019, the entry of protac targeting AR and ER into clinical trials is undoubtedly a real milestoneAlso in this year, a team developed the optical control protac< br / > scientists have found more than 600 E3 ligases in the human genome, and only a few of them have been used in protac designThe ligands of crbn, VHL, MDM2, IAPs, dcaf15, dcaf16, RNF4 and rnf114 E3 ligases are mainly used in the development of anticancer protacTable 1 below summarizes the key anti-cancer targets successfully targeted by small molecule protacs developed with these E3 ligandsCompared with the traditional small molecule inhibitors (SMIS), protacs have several advantages related to their unique mechanism of actionIts main advantages include its catalytic type, high selectivity, the potential of targeting non proprietary proteins and the ability to overcome the resistance of small molecule inhibitors by targeting mutant proteinsIn addition, by using ligands of tissue-specific and / or tumor selective E3 ligases, protocs may achieve tumor specific / selective degradation of the target protein Because of these properties, Protecs avoids many side effects and limitations of small molecule inhibitors However, there are still some safety issues related to protacs (including on target and off target toxicity) to be considered before promoting clinical transformation Table 2 below summarizes the advantages and disadvantages of protacs and small molecule inhibitors < br / > < br / > < br / > Figure 3 summarizes the tissue expression characteristics of E3 ubiquitin linker The researchers found that some E3 ligases showed significant aggregation in tissues such as the brain, muscles and testes At the same time, the analysis showed that 3% of E3 ligase could not be detected in almost all normal tissues, 9% of E3 ligase was low expressed in almost all normal tissues, 4% of E3 ligase was high expressed in almost all normal tissues (FIG 4A; table 3), and about 9% of E3 ligase was specifically expressed in one tissue (Fig 4B showed that klhl41 was specifically expressed in skeletal muscle, Rnf112 is mainly expressed in brain tissue, while trim69 is specifically expressed in testis 12% of E3 ligase is enriched in 2-7 tissue types (FIG 4A) These findings indicate that some E3 ligases have tissue selective expression patterns in normal human tissues These E3 ligases may be used to design tissue-specific or selective protacs < br / > < br / > < br / > < br / > < br / / > up to now, most protocs have been developed using ligands that can recruit E3 ligases that are widely expressed in tumor and normal tissues If the interest proteins (target proteins) are not tumor specific, then these protocs will lead to miss target toxicity Therefore, the identification of E3 linkers that are enriched in tumors but expressed very low in normal tissues will be helpful for the development of tumor specific / selective protacs As shown in Table 3 below, 69 E3 ligases meet the standard (column 3) < br / >, For example, protocs targeting Brd4, Btk, bcrabl and cdk-6 have shown the potential to treat leukemia; rotacs targeting AR, er, FAK and p38 are being developed to treat a variety of different solid tumors; protocs targeting Bcl-xL and alk also show a wide range of antitumor activity, which can effectively kill leukemia and solid tumor cells in vitro and in xenotransplantation models However, as the molecular weight of protacs is larger than that of small molecule inhibitors (the size of a good small molecule drug is usually less than 500 daltons, but at present, the size of protacs is more than 1000 daltons), tissue permeability and cell permeability are still major challenges < br / > with the disclosure of some key clinical data, the development of new anticancer therapy based on protacs technology has entered a new stage Protocs and similar compounds may represent a new class of drugs different from chemotherapy, small molecule inhibitors, antibodies and cell therapy
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