2. Academic Validation
  3. Development of photocontrolled BRD4 PROTACs for tongue squamous cell carcinoma (TSCC)

Development of photocontrolled BRD4 PROTACs for tongue squamous cell carcinoma (TSCC)

  • Eur J Med Chem. 2021 Oct 15:222:113608. doi: 10.1016/j.ejmech.2021.113608.
Zhenzhen Li 1,  Siyue Ma 1,  Xingye Yang 1,  Ling Zhang 1,  Dong Liang 1,  Gaopan Dong 1,  Lupei Du 2,  Zhenghua Lv 3,  Minyong Li 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 2 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: dulupei@sdu.edu.cn.
  • 3 Department of Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250022, China. Electronic address: entlvzhenghua@163.com.
  • 4 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: mli@sdu.edu.cn.
PMID: 34119833 DOI: 10.1016/j.ejmech.2021.113608
Abstract

The catalytic properties of small-molecule proteolysis targeting chimeras (PROTACs) may lead to uncontrolled degradation. Therefore, the main disadvantages of PROTACs are non-cancer specificity and relatively high toxicity, which limit the clinical application of PROTACs. The photocontrolled PROTACs (photoPROTACs) were proposed to overcome this issue, in which they can be triggered by ultraviolet A (UVA) or visible light to induce the degradation of the target protein. Herein, we designed several photoPROTACs to cause the degradation of bromodomain-containing protein 4 (BRD4) on-demand using 365 nm light. The representative compound N2 is proved to induce the degradation of BRD4 upon irradiation. Moreover, compound N2 was successfully applied in vivo to inhibit tumor growth in a zebrafish xenograft model of skin Cancer tongue squamous cell carcinoma (TSCC) in a photocontrol manner.

Keywords

BRD4; PhotoPROTACs; Protein degradation; Tongue squamous cell carcinoma; UVA.

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