2. Academic Validation
  3. Design and Synthesis of Novel Deazapurine DNMT 1 Inhibitors with In Vivo Efficacy in DLBCL

Design and Synthesis of Novel Deazapurine DNMT 1 Inhibitors with In Vivo Efficacy in DLBCL

  • J Med Chem. 2025 Mar 13;68(5):5333-5357. doi: 10.1021/acs.jmedchem.4c02391.
Linyu Yang 1,  Tao Yang 2,  Yi Wen 1,  Minghai Tang 1,  Yaxin Teng 1,  Wanhua Zhang 1,  Yunhua Zheng 3,  Lijuan Chen 1,  Zhuang Yang 1
Affiliations

Affiliations

  • 1 Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
  • 2 Laboratory of Natural and Targeted Small Molecule Drugs and National Chengdu Center for Safety Evaluation of Drugs, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
  • 3 Department of Quality Evaluation and Medical Record Management, The Affiliated Hospital of Southwest Jiaotong University & The Third People's Hospital of Chengdu, Chengdu, Sichuan 610000, China.
PMID: 40022722 DOI: 10.1021/acs.jmedchem.4c02391
Abstract

The application of drugs to regulate abnormal epigenetic changes has become an important means of tumor treatment. In this study, we employed computer-aided design methods to develop a novel deazapurine compound targeting DNA Methyltransferase 1 (DNMT1). Through screening for Enzyme activity, selectivity, and cellular efficacy, we optimized three structural skeletons, ultimately yielding compound 55, exhibiting an IC50 of 2.42 μM for DNMT1. Compound 55 displayed excellent in vitro inhibitory effects on various hematological tumor and solid tumor cell lines, especially lymphoma cells, with IC50 values in the nanomolar range. In vitro studies confirmed compound 55 selectively inhibited DNMT1 and exhibited demethylation ability. In vivo mouse model validated the DNA methylation inhibition of compound 55. Compound 55 demonstrated good antitumor activity in vivo. Specifically, compound 55 combined with chidamide demonstrated a superior therapeutic effect over the first-line therapy RTX-CHOP in both the DEL and TP53 mutant DLBCL PDX tumor models.

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