Design and Synthesis of Novel Deazapurine DNMT 1 Inhibitors with <i>In Vivo</i> 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 <b>55,</b> exhibiting an IC₅₀ of 2.42 μM for DNMT1. Compound <b>55</b> displayed excellent <i>in vitro</i> inhibitory effects on various hematological tumor and solid tumor cell lines, especially lymphoma cells, with IC₅₀ values in the nanomolar range. <i>In vitro</i> studies confirmed compound <b>55</b> selectively inhibited DNMT1 and exhibited demethylation ability. <i>In vivo</i> mouse model validated the DNA methylation inhibition of compound <b>55</b>. Compound <b>55</b> demonstrated good antitumor activity <i>in vivo</i>. Specifically, compound <b>55</b> 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.