Review
Recent Advances in PROTAC Technology Toward New Therapeutic Modalities
Dr. Hidetomo Yokoo,
Miyako Naganuma,
Prof. Makoto Oba,
Dr. Yosuke Demizu,
Corresponding Author
Dr. Hidetomo Yokoo
Medical Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo Hangicho, Sakyo-ku, Kyoto, 606-0823 Japan
Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa, 210-9501 Japan
Search for more papers by this authorMiyako Naganuma
Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa, 210-9501 Japan
Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045 Japan
Search for more papers by this authorProf. Makoto Oba
Medical Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo Hangicho, Sakyo-ku, Kyoto, 606-0823 Japan
Search for more papers by this authorCorresponding Author
Dr. Yosuke Demizu
Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa, 210-9501 Japan
Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045 Japan
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushimanaka, Kita-ku, Okayama, 700-8530 Japan
Search for more papers by this authorDr. Hidetomo Yokoo,
Miyako Naganuma,
Prof. Makoto Oba,
Dr. Yosuke Demizu,
Corresponding Author
Dr. Hidetomo Yokoo
Medical Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo Hangicho, Sakyo-ku, Kyoto, 606-0823 Japan
Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa, 210-9501 Japan
Search for more papers by this authorMiyako Naganuma
Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa, 210-9501 Japan
Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045 Japan
Search for more papers by this authorProf. Makoto Oba
Medical Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo Hangicho, Sakyo-ku, Kyoto, 606-0823 Japan
Search for more papers by this authorCorresponding Author
Dr. Yosuke Demizu
Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki, Kanagawa, 210-9501 Japan
Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045 Japan
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushimanaka, Kita-ku, Okayama, 700-8530 Japan
Search for more papers by this authorAbstract
Proteolysis targeting chimeras (PROTACs) have emerged as a powerful technology for the degradation of disease-related proteins by the hijacking of the endogenous ubiquitin-proteasome system. A multitude of bifunctional PROTACs have been developed using small-molecule ligands; one ligand binds to the target protein of interest and one ligand binds to an E3 ligase. The characteristics of those PROTACs vary, including their reversible or irreversible covalent binding to the target protein, their binding to orthosteric and allosteric sites, their agonist or antagonist activity, and their use of multiple ligands. In addition, oligopeptides and nucleotides have recently been used as alternative targeting ligands. The properties of PROTACs, such as selectivity, delivery and sensitivity to drug resistance, can be improved through the use of a variety of targeting ligand modalities. This minireview introduces the mechanisms and behavior of small-molecule based PROTACs as well as targeted proteolysis techniques using peptides and nucleic acids as targeting ligands.
Graphical Abstract
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