2. Academic Validation
  3. Photo-regulated PROTACs: A novel tool for temporal control of targeted protein degradation

Photo-regulated PROTACs: A novel tool for temporal control of targeted protein degradation

  • Bioorg Med Chem Lett. 2024 Jul 15:107:129778. doi: 10.1016/j.bmcl.2024.129778.
Hanqiao Xu 1,  Nobumichi Ohoka 2,  Takao Inoue 3,  Hidetomo Yokoo 4,  Yosuke Demizu 5
Affiliations

Affiliations

  • 1 Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Yokohama, Kanagawa 230-0045, Japan; Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan.
  • 2 Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan. Electronic address: n-ohoka@nihs.go.jp.
  • 3 Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan.
  • 4 Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan. Electronic address: yokoo@nihs.go.jp.
  • 5 Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Yokohama, Kanagawa 230-0045, Japan; Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Division of Pharmaceutical Science of Okayama University, 1-1-1 Tsushimanaka, Kita, Okayama 700-8530, Japan. Electronic address: demizu@nihs.go.jp.
PMID: 38702019 DOI: 10.1016/j.bmcl.2024.129778
Abstract

PROTACs (Proteolysis targeting chimeras) are chimeric molecules designed to induce targeted protein degradation via the ubiquitin-proteasome system. These molecules catalytically degrade target proteins and sustainably inhibit their function. Therefore, PROTAC's unique mechanism of action is not only beneficial in medicine but also serves as a valuable tool for molecular biological analysis in fields like chemical biology, biochemistry, and drug discovery. This study presents a novel turn-off (ON-OFF) type PROTAC development strategy utilizing a photocleavable linker. The inclusion of this linker enables temporal control of the degradation activity targeting BRD4 protein upon UV LIGHT exposure. PROTAC-2 demonstrated the most potent degradation activity against BRD4 among the other synthesized PROTACs with varying linker lengths. The UV light-induced cleavage of PROTAC-2 was confirmed, leading to a reduction in its BRD4 degradation activity. Notably, this study introduces a novel linker capable of nullifying degradation activity of PROTACs which is activated by LIGHT irradiation. These findings offer a promising strategy for the development of turn-off type PROTACs, providing enhanced temporal control over protein degradation. The approach holds significant potential for applications in molecular function studies and drug discovery.

Keywords

Chemical tool; PROTAC; Photo-caged group; Photocleavable linker; Turn-off type.

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