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

Anqi Li; Wenwen Zheng; Boren Xiao; Wenjun Huang; Lulu Li; Minglang Luo; Zijian Liu; Bizhu Chu; Yuyang Jiang

doi:10.1016/j.bmcl.2023.129466

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. Epub 2023 Sep 1.

Authors

Anqi Li¹, Wenwen Zheng², Boren Xiao¹, Wenjun Huang², Lulu Li³, Minglang Luo³, Zijian Liu⁴, Bizhu Chu⁵, Yuyang Jiang⁶

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: liuzijian1115@163.com.
⁵ School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China. Electronic address: chubz@szu.edu.cn.
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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Histone Deacetylase Inhibitors* / pharmacology
Humans
Hydroxamic Acids / pharmacology
Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
Pyrimidines / pharmacology

Substances

Histone Deacetylase Inhibitors
Hydroxamic Acids
Pyrimidines
KDM6B protein, human
Jumonji Domain-Containing Histone Demethylases
Antineoplastic Agents