The novel hypomethylating agent NTX-301 reprograms epigenetic and Hippo signaling pathways and exhibits pre-clinical activity in venetoclax-resistant and TP53-mutant AML

We investigated therapeutic efficacy and mechanisms of action of NTX-301, a next-generation HMA and demonstrate that NTX-301 is superior to 5-azacytidine (5-AZA), exhibits activities in 5-AZA or VEN-resistant AML and synergizes with VEN in VEN or VEN/HMA resistant and TP53-mutant AML blasts and stem/progenitor cells both, in vitro and in vivo in PDX models.

NTX-301 inhibits DNMT1 and increases p73, caspase-8, and activated caspase-8 in TP53-WT and TP53-mutant cells and activates p53 signaling. Methylation profiling analyses revealed that NTX-301 is a more selective hypomethylating agent compared to 5-AZA. Pathway analysis of 954 commonly hypomethylated genes showed profoundly greater enrichment of Hippo signaling in NTX-301-treated compared to 5-AZA-treated cells, and enrichment of insulin signaling, VEGF pathway, and cell cycle selectively in NTX-301- but not in 5-AZA-treated cells.