2. Academic Validation
  3. Design, synthesis and biological evaluation of pyrimidine base hydroxamic acid derivatives as dual JMJD3 and HDAC inhibitors

Design, synthesis and biological evaluation of pyrimidine base hydroxamic acid derivatives as dual JMJD3 and HDAC inhibitors

  • Bioorg Med Chem Lett. 2023 Oct 1:94:129466. doi: 10.1016/j.bmcl.2023.129466.
Anqi Li 1,  Wenwen Zheng 2,  Boren Xiao 1,  Wenjun Huang 2,  Lulu Li 3,  Minglang Luo 3,  Zijian Liu 4,  Bizhu Chu 5,  Yuyang Jiang 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Tsinghua University, Beijing 100084, China.
  • 2 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
  • 3 State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China.
  • 4 Shenzhen Bay Biopharm Co., Ltd, Shenzhen 518057, China; Shenzhen Winkey Technology Co., Ltd, Shenzhen 518055, China. Electronic address: [email protected].
  • 5 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China. Electronic address: [email protected].
  • 6 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China; State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518132, China.
PMID: 37660833 DOI: 10.1016/j.bmcl.2023.129466
Abstract

The Jumonji domain-containing protein demethylase 3 (JMJD3) and histone deacetylase (HADC) are related to various cancers and regard as antitumor targets for drug discovery. In this study, based on rational drug design strategy, we designed and synthesized a series of pyrimidine derivatives with hydroxamic acid as novel dual JMJD3 and HDAC inhibitors for synergistic Cancer treatment. Compound A5b exhibited inhibitory potency against JMJD3 and HDAC1/6 simultaneously and favorable cytotoxicity against human Cancer cells such as A549 and U937. Furthermore, mechanistic studies showed that A5b treatment in A549 cells increased the hypermethylation of histone H3K27 and hyperacetylation of H3K9, suppressed clonogenicity, migration and invasion of Cancer cells. Besides, A5b induced Apoptosis via the cleavage of caspase-7 and PARP, and G1 cell cycle arrest via upregulated p21 expression. All these results suggested that A5b was the first dual inhibitor against JMJD3 and HDAC and can be a potential compound for Cancer therapy.

Keywords

Antitumor; Dual inhibitor; HDAC; JMJD3; Structure activity relationship analysis.

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