Design, Synthesis and Biological Evaluation of <scp>POLRMT</scp> Inhibitors for the Treatment of Acute Myeloid Leukemia

The metabolic dependence of acute myeloid leukemia (AML) cells on mitochondrial oxidative phosphorylation (OXPHOS) has become a cutting-edge area in cancer energy metabolism research, playing a pivotal role in cell survival and drug resistance. Consequently, targeted inhibition of human mitochondrial RNA polymerase (POLRMT) to block mitochondrial gene expression emerges as a novel potential strategy for treating AML through OXPHOS modulation. In this study, based on the previously reported crystal structure of the POLRMT inhibitor IMT1B, we employed a scaffold hopping strategy to design and synthesize a series of derivatives featuring additional hydrophobic occupying groups. A new potent POLRMT inhibitor (10a) was discovered, which displayed potent antiproliferative activity and could disrupt mitochondrial function and induce apoptosis in MOLM-13 cells. Together, these results demonstrate that 10a is a new POLRMT inhibitor, which may provide a candidate lead for AML treatment.