A Study on Preclinical Efficacy, Underlying Mechanisms, and Sensitivity Markers of a Novel Hypomethylating Agent Ntx-301 in Acute Myeloid Leukemia

Introduction: While intensive induction chemotherapy has been standard-or-care for patients with acute myeloid leukemia (AML), intensive regimens have often been limited in elderly patients with comorbidities. As an alternative option, less intensive hypomethylating agents (HMAs), decitabine (DAC) and azacitidine (AZA), are currently being used in these unfit patients. However, their low response rates and adverse events when administered alone suggest a need to develop novel HMAs that elicit enhanced efficacy and reduced mortality. A recent study demonstrated pharmacological improvements of a novel 4′-thio-modified analog, 5-aza-4′-thio-2′-deoxycytidine (hereafter NTX-301), including enhanced chemical stability and incorporation into DNA and improved preclinical efficacy (Thottassery, 2014). However, the mechanism of action (MoA) of NTX-301 has not yet been understood. Herein, we aim to thoroughly investigate the preclinical efficacy and MoAs of NTX-301 in AML through comparative analysis with DAC and AZA. To this end, we used in vitro and in vivo preclinical models of AML and performed multiomics-based analyses.