Abstract 6282: EP102: Pharmacological inhibition of METTL3 arrests tumor progression and prolongs survival in CDX and PDX models of AML

METTL3 is the RNA methyltransferase predominantly responsible for the addition of N-6-methyladenosine (m6A), the most abundant modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML)1. EPICS has discovered and optimized a small molecule inhibitor of METTL3 (“M3i”). M3i was shown to inhibit the enzymatic activity of METTL3 (IC50 = 2 nM, SPA assay) and inhibit the presence of intracellular m6A in a cell-based assay (IC50 = 8 nM, Calu6). The anti-proliferative effects of METTL3 was demonstrated in a spheroid model (NCIH-560, IC50 = 100 nM) as well as cell viability assays in various AML (Kasumi-1, IC50 = 30 nM; LEXF 41283, IC50 = 46 nM; MV-4-11, IC50 = 248 nM) and solid tumor (Calu6, IC50= 6 nM; Caov3, IC50 = 27 nM) cell lines. In vivo efficacy was evaluated in a disseminated xenograft model using established systemic MV-4-11-Luc-mCh-Puro2 in female NSG mice where M3i (30 mg/kg, i.p., QDx31 days) significantly (p