2. Academic Validation
  3. Selective degradation of cellular BRD3 and BRD4-L promoted by PROTAC molecules in six cancer cell lines

Selective degradation of cellular BRD3 and BRD4-L promoted by PROTAC molecules in six cancer cell lines

  • Eur J Med Chem. 2023 Jun 5;254:115381. doi: 10.1016/j.ejmech.2023.115381.
Ziqin Yan 1,  Xilin Lyu 1,  Dongze Lin 2,  Gaoxing Wu 3,  Yang Gong 4,  Xuelian Ren 5,  Jian Xiao 6,  Jianfeng Lou 3,  He Huang 7,  Yi Chen 8,  Yujun Zhao 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China.
  • 2 Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China.
  • 3 State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • 4 State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, China.
  • 5 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China.
  • 6 University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China; Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China.
  • 7 University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China.
  • 8 Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China. Electronic address: ychen@simm.ac.cn.
  • 9 State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China; Shandong Provincial Key Laboratory of Biopharmaceuticals, Shandong Academy of Pharmaceutical Sciences, Jinan, 250101, China. Electronic address: yjzhao@simm.ac.cn.
PMID: 37084596 DOI: 10.1016/j.ejmech.2023.115381
Abstract

Targeted degradation of BET family proteins BRD2/3/4 or only BRD4 with PROTAC molecules has been a promising strategy for the treatment of human Cancer. Meanwhile, selective degradation of cellular BRD3 and BRD4-L remains a challenging task. We report herein a novel PROTAC molecule 24 that promoted selective degradation of cellular BRD3 and BRD4-L, but not BRD2 or BRD4-S, in a panel of six Cancer cell lines. The observed target selectivity was partially attributed to differences in protein degradation kinetics and in types of cell lines. In a MM.1S mouse xenograft model, an optimized lead compound 28 promoted selective degradation of BRD3 and BRD4-L in vivo and exhibited robust antitumor activity. In summary, we have demonstrated that selective degradation of BRD3 and BRD4-L over BRD2 and BRD4-S is a feasible and robust approach in multiple Cancer cell lines and an animal model, which could be helpful for further investigations on BRD3 and BRD4-L that ultimately benefitting Cancer research and therapeutics.

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