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  3. Structure-Based Discovery of Selective Histone Deacetylase 8 Degraders with Potent Anticancer Activity

Structure-Based Discovery of Selective Histone Deacetylase 8 Degraders with Potent Anticancer Activity

  • J Med Chem. 2022 Dec 14. doi: 10.1021/acs.jmedchem.2c00739.
Jinbo Huang 1 2 3,  Jun Zhang 1 2 3,  Wenchao Xu 4,  Qiong Wu 1 2 3,  Rongsheng Zeng 4,  Zhichao Liu 1 2 3,  Wenhui Tao 1 2 3,  Qian Chen 1 2 3,  Yongqing Wang 5,  Wei-Guo Zhu 1 2 6 4 3
Affiliations

Affiliations

  • 1 Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, and International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518055, China.
  • 2 Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518055, China.
  • 3 Health Science Centre School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China.
  • 4 Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen 518055, China.
  • 5 Division of Rheumatology and Immunology, University of Toledo Medical Center, 3120 Glendale Avenue, Toledo 43614, Ohio, United States.
  • 6 Shenzhen Bay Laboratory, Shenzhen University School of Medicine, Shenzhen 518055, China.
PMID: 36516047 DOI: 10.1021/acs.jmedchem.2c00739
Abstract

Inducing protein degradation by proteolysis targeting chimeras has gained tremendous momentum as a promising novel therapeutic strategy. Here, we report the design, synthesis, and biological characterization of highly potent proteolysis targeting chimeric small molecules targeting the epigenetic regulator histone deacetylase 8 (HDAC8). We developed potent and effective HDAC8 degraders, as exemplified by SZUH280 (16e), which effectively induced HDAC8 protein degradation and inhibited Cancer cell growth even at low micromolar concentrations. Our preliminary mechanistic studies revealed that SZUH280 hampers DNA damage repair in Cancer cells, promoting cellular radiosensitization. In mice, a single SZUH280 dose induced rapid and prolonged HDAC8 protein degradation in xenograft tumor tissues. Moreover, SZUH280 alone or in combination with irradiation resulted in long-lasting tumor regression in an A549 tumor mouse model. Our findings qualify a new chemical tool for HDAC8 knockdown and may lead to the development of a new class of Cancer therapeutics.

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