"Nature" published a new design strategy for PROTAC molecules, significantly improving protein degradation efficiency and anti-cancer activity

▎The content team editor of WuXi AppTec.
Targeted protein degradation therapy represented by PROTAC has been a hot area of ​​new drug development in recent years
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This strategy may not only solve the resistance to traditional small molecule inhibitors, but also target a variety of "non-drugable" targets
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Today, a scientific paper published in Nature Chemical Biology, a sub-issue of "Nature", demonstrated the new design strategy of PROTAC molecules
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Studies have found that a trivalent molecule containing three protein binding domains can better bind to the target protein, which not only improves the efficiency of protein degradation, but also improves the anti-cancer activity of the compound in in vitro experiments
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PROTAC is a bifunctional molecule.
One end of it can bind to a specific target protein, and the other end can recruit E3 ubiquitin ligase, tag the target protein with ubiquitin, and allow them to be degraded by the cell's proteasome
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How to optimize the design of PROTAC molecules to make them more effectively bind to the target protein and mediate protein degradation is an important direction for drug developers
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In this study, researchers optimized the design of PROTAC molecules with bromodomain and extra terminal domain (BET) family proteins as targets
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BET family proteins play an important role in epigenetic regulation, and BET inhibitors have shown therapeutic activity in preclinical models of cancer and inflammatory diseases
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Previous studies have found that a PROTAC molecule named MZ1 can bind to the BET family protein BRD4 and E3 ubiquitin ligase VHL to mediate the degradation of BRD4
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Another BET inhibitor called MT1 can bind to two BRD4 proteins
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Based on the crystal structure of BRD4-MZ1-VHL, the researchers designed a trivalent molecule that carries two binding domains that bind to the BET protein and one binding domain that binds to the E3 ubiquitin ligase
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▲The design principle of the trivalent PROTAC molecule (picture source: reference [1]) After further screening, the researchers selected a trivalent PROTAC molecule called SIM1
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Compared with the existing bivalent PROTAC molecule MZ1, the efficiency of degrading BRD2 protein is increased by 300 times
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Moreover, in cancer cell lines that are sensitive to BET inhibitors, SIM1 induces apoptosis more effectively
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▲The trivalent PROTAC molecule more effectively induces apoptosis of cancer cell lines (picture source: Reference [1]) The researchers pointed out in the discussion section of the paper that the PROTAC molecule can form a stable ternary with the target protein and E3 ligase The ternary complex is the key to improving the efficiency of protein degradation
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This study shows that trivalent PROTAC molecules can effectively generate stable ternary complexes and improve protein degradation efficiency by improving the avidity and cooperativity of the molecules
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▲The diagram of this study (picture source: Reference [1]) Changing the divalent PROTAC molecule to the trivalent PROTAC molecule brings greater challenges to chemical synthesis, and the molecular weight of the trivalent PROTAC molecule is larger, and their cell penetration Sexual and pharmacokinetic characteristics may be impaired
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Therefore, synthesizing trivalent PROTAC molecules is not an effective strategy to improve PROTAC molecules at first glance
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However, this study shows that these challenges can be overcome.
Although the cell permeability of the trivalent PROTAC molecule SIM1 is weaker than that of the bivalent molecule, it shows better therapeutic potential in the detection of related cell lines
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Moreover, this molecule also showed good pharmacokinetic characteristics in animal experiments
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The researchers said that the trivalent PROTAC molecule provides a new strategy for the design of PROTAC, which is expected to significantly improve multiple indicators of protein degradation.
In the future, it may be used to target a wider range of protein targets, including "non-drugable" targets
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Reference: [1] Imaide et al.
, (2021).
Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity.
Nature Chemical Biology, https://doi.
org/10.
1038/s41589-021-00878-4[2] Research Reveals Trivalent PROTACs More Potent in Targeted Protein Degradation.
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