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
  • 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: [email protected].
  • 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: [email protected].
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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