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

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.