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    Home > Biochemistry News > Biotechnology News > PROTAC's latest review: Focus ingesting on cancer

    PROTAC's latest review: Focus ingesting on cancer

    • Last Update: 2020-06-16
    • Source: Internet
    • Author: User
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    PROTACs, known as Proteolysis-Targeting Chimeras, are protein hydrolysis-targeted clycosines with a structure that looks like dumbbells and connects "the ligand of the interest protein" and the "recruitment ligand of E3 unonosininconnectase" through a "linker"In other words, one end of the PROTACs molecule binds to the interest protein (i.ethe target protein) and the other end to the E3 ubiquitin joinulaThe E3 ubiquitin connecting enzyme seisy can label a small protein called a ubiquitin as a defective or damaged protein by attaching it to the target proteinThe cell's protein shredder (i.e., protease) then processes the labeled target proteinWith the world's first small molecule protein degradation agent, ARV-110, developed based on PROTACs, revealing positive Phase I clinical data, the industry's heat has increased further, and several pharmaceutical and biotechnology companies have laid out the technologyAlthough there is a promising treatment for a wide range of diseases, proTACs are currently being investigated for the potential of drugs used to treat cancerSource: Oncogene, May 31, a team of scientists from the University of Florida in the United States, a new review published in nature's Oncogene journal, focuses on new anti-cancer therapies based on PROTACsThe authors point out that the use of PROTACs to degrade proteins critical to tumor development has become a potential cancer treatment strategySince its first discovery in 2001, PROTACs technology has been developed to target a wide range of cancer targetsIn this article, they discussed the potential and safety of PROTACs as an anticancer therapy, with particular attention to the development of tumor-specific/selective PROTACsThe following is based on the chart in the article, excerpted some of the main points: "1) :P 3 types of ROTACs Instituated 1 PROTACs mediated protein degradation mechanism (Source: Oncogene) Figure 1 explains the proTACs mediated protein degradation mechanism, divided into 3Figure a is a diagram of the general mechanism of PROTAC inducing protein degradation of interestAs mentioned earlier, PROTAC molecules are labeled by a large number of ubiquitin molecules by recruiting E3 ubiquitin synthase to interest proteinsAfter that, polyphenomenosis is identified by protease and degradedThe PROTAC molecule is then recycled to induce the next round of degradationFigure b explains the mechanism by which homo-PROTACs mediate the self-degradation of E3 connectivases (self-degradation)A homo-PROTAC recruits an E3 connecting enzyme molecule (e.gCRBN or VHL) to another E3 connecting enzyme molecule, followed by two-way polyphertization of the E3 connecting enzyme molecule, which is then degraded by both moleculesFigure c explains the mechanism by which photo-PROTACs mediate protein degradation in photo-pro-Photo-ProTACsIn photo-PROTAC, a photoremovable group is attached to an interest ligand or E3 connected enzyme ligand or "linker"After external light exposure, the light movable group is separated from the photo-PROTAC and converted into active PROTAC for interest protein degradationKey point (2) :P ROTACs Discovery Milestone SProTACs Discovery Milestone (Source: Oncogene) PROTACs Research Area is relatively new, but rapidlyFigure 2 summarizes some important advances in the technology since it was first discovered in 2001If the first small molecule PROTAC was reported in 2008 as an important turning point in the development of the field, then the entry of PROTAC targeting AR and ER into clinical trials in 2019 is undoubtedly a true milestoneAlso in the same year, a team developed light control PROTACKey point (3): 8 commonly used E3 netonoases and more than 20 anti-cancer targets Scientists have found more than 600 E3 connecting enzymes in the human genome, only a few of which are used in PROTAC designAnti-cancer PROTAC was developed using the ligands of CRBN, VHL, MDM2, IAPs, DCAF15, DCAF16, RNF4 and RNF114 E3Table 1 below summarizes the key cancer targets successfully targeted by PROTACs, a small molecule developed using these E3 netolas ligandsSource: Oncogene Point (4) :P the advantages and disadvantages of ROTACs compared to traditional small molecule inhibitors (SMIs), PROTACs have several advantages associated with their unique mechanisms of actionIts main advantages include its catalytic type, high selectivity, the potential of targeting non-essential pharmaceutical proteins, and the ability to overcome small molecule inhibitor resistance by targeting mutant proteinsIn addition, PROTACs may achieve tumor-specific/selective degradation of the target protein by using tissue-specific and/or tumor-selective E3 ligase ligations Because of these properties, PROTACs avoid many side effects and limitations of small molecule inhibitors However, there are still some proTACs-related safety issues (including on-target and off-target toxicity) that need to be considered before clinical conversion is promoted Table 2 below summarizes the advantages and disadvantages of PROTACs and small molecule inhibitors Source: Oncogene Point (5): E3 Connecting Enzyme Tissue Expression Characteristics Figure 3 summarizes the tissue expression characteristics of E3 ubiquitin linked enzymes The researchers found that some E3 connectivases showed significant aggregation in some tissues, such as the brain, muscles and testes At the same time, the analysis showed that 3% of E3 connecting enzymes were undetectable in almost all normal tissues, 9% of E3 connecting enzymes were low expressed in almost all normal tissues, 4% of E3 nemesases were expressed in almost all normal tissues (Figure 4a; Table 3), and about 9% of E3 connecting enzymes expressed specificity in one tissue (in almost normal tissues) As shown in Figure 4b, KLHL41 is specifically expressed in skeletal muscle, RNF112 is expressed mainly in brain tissue, while TRIM69 is specifically expressed in the testes, and 12% of E3 luteses are enriched in 2-7 tissue types (Figure 4a) These findings suggest that some E3 connecting enzymes have tissue selective expression patterns in normal human tissues These E3 joinases may be used to design tissue-specific or selective PROTACs Figure 3 E3 connecting enzyme expression characteristics in normal tissue (Source: Oncogene) Figure 4 E3 connecting enzymedistribution in normal tissue (Source: Oncogene) Key points (6): 69 tumor-specific/selective E3 connecting enzymes So far, most PROTACs have developed a dispensing of E3 connectivase that can be widely expressed in tumors and normal tissues, if the interest protein (target) is not tumor-specific Therefore, identifying E3 linked enzymes that are rich in tumors but expressed very low in normal tissues will help develop tumor-specific/selective PROTACs As shown in Table 3 below, 69 E3 joinulas meet the criteria (column 3) Source: Oncogene Figure 5 Tumor-specific/Selective E3 Collyenzyme Identification (Source: Oncogene) Summary PROTACs have been developed to fight different targets for solid tumors and malignant blood cancers and have shown high efficacy for certain tumor cells in a targeted dependion, such as targeting targets such as BRD4, BTK, BCRABL and CDK-6 PROTACs have shown potential for the treatment of leukemia, while ROTACs targeting AR, ER, FAK, P38 are being developed to treat many different solid tumors, and PROTACs targeting BCL-XL and ALK have also demonstrated broad-spectrum antitumor activity that can effectively kill leukemia and solid tumor cells in both in vitro and heterotransplantmodels However, since proTACs have a larger molecular weight than small molecular inhibitors (a good small molecule drug is usually less than 500 Daltons, but currently PROTACs are more than 1000 Daltons), tissue permeability and cell penetration remain major challenges With the disclosure of some key clinical data, the development of new anticancer therapies based on PROTACs technology has entered a new phase PROTACs and similar compounds may represent a new class of drugs that differ from chemotherapy, small molecule inhibitors, antibodies, and cell therapy Related paper: Sajid Khan et al PROteolysis TArgeting Chimeras (PROTACs) as emerging anti-therapeuticcancers Oncogene (2020) Kathleen M Sakamoto et al Protacs: Chimeric molecules that target stos to the Skp1-Cullin-F box complex for the ubiquitination and the sydd PNAS (2001) Ashley R Schneekloth et al intra Targetedcellular protein ath rhyllseth by asmall molecule: En route to chemical chemical proteoprotemics Bioorganic and Thepost Chemistry Letters (2008).
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