著者

大岡 伸通 井上 貴雄

出版者

公益社団法人 日本薬剤学会

雑誌

薬剤学 (ISSN:03727629)

巻号頁・発行日

vol.82, no.2, pp.71-78, 2022 (Released:2022-04-01)

参考文献数

10

著者

大岡 伸通

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.138, no.9, pp.1135-1143, 2018-09-01 (Released:2018-09-01)

参考文献数

28

被引用文献数

6

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Protein knockdown technologies based on small molecules are attracting considerable attention in the pharmaceutical industry as a strategy for novel drug discovery. We and others have developed such compounds, designated as Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs), proteolysis-targeting chimeras (PROTACs), and Degronimids, which induce selective degradation of target proteins. These compounds contain two different ligands, specific for an ubiquitin E3 ligase and for a target protein, respectively, connected by a linker. SNIPERs, PROTACs, and Degronimids are designed to cross-link E3 ligase and the target protein to induce polyubiquitylation and proteasomal degradation of the target protein within cells. To recruit the von Hippel-Lindau (VHL) E3 ligase complex and the cereblon (CRBN) E3 ligase complex, a VHL inhibitor and a thalidomide derivative have been integrated into PROTAC and Degronimid constructs, respectively. Similarly, an IAP antagonist has been incorporated into SNIPERs to recruit cellular inhibitor of apoptosis protein 1 (cIAP1) or X-linked inhibitor of apoptosis protein (XIAP) E3 ligase. To date, a range of such compounds have been developed, allowing selective degradation of a variety of proteins, including estrogen receptor α (ERα), oncogenic kinase BCR-ABL, and epigenetic regulator bromodomain-containing protein 4 (BRD4). Some compounds have also demonstrated ability to degrade target proteins in vivo, suggesting that this technology is feasible for use in novel drug development.

著者

大岡 伸通 内藤 幹彦

出版者

公益社団法人 日本薬学会

雑誌

ファルマシア (ISSN:00148601)

巻号頁・発行日

vol.56, no.1, pp.41-45, 2020 (Released:2020-01-01)

参考文献数

20

被引用文献数

1

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近年、細胞内の狙ったタンパク質を特異的に分解する化合物を創製する技術が開発され、新しい低分子薬の創薬モダリティとして製薬業界やアカデミアを中心に大きな注目を集めている。本稿では、これらの化合物の総称として定着しつつあるPROTAC(Proteolysis-targeting Chimera)の開発経緯、医薬品開発企業の動向、従来の低分子薬とは異なる特徴や将来の展望などについて概説する。