N 6 -methyladenosine (m 6 A) is the most prevalent modification of eukaryotic mRNA and plays a crucial role in gene regulation. Methyltransferase-like 3 (METTL3), the key catalytic component of the m 6 A methyltransferase complex, is primarily responsible for depositing m 6 A on target RNA. METTL3 is highly expressed in various cancers and is closely associated with tumor development. Previous studies have also shown that METTL3 inhibition activates anti-tumor immunity and reshapes the tumor microenvironment. Using structure-based drug design owing to the generation of multiple high resolution crystal structures of ligands bound to the METTL3-METTL14 complex, we developed novel METTL3 inhibitors. This effort led to the identification of ASTU-045, a selective METTL3 inhibitor that demonstrated cellular target engagement (m 6 A inhibition) and, in an in vitro co-culture system, showed strong, concentration dependent enhancement of PBMC-mediated killing of cancer cells. In the MC38 colorectal syngeneic model, oral administration of ASTU-045 to immune-competent, tumor-bearing mice resulted in tumor stasis. Combination treatment with ASTU-045 and an anti-PD1 antibody produced significant tumor regression. Strong target engagement was also observed in the spleen under both treatment conditions. In summary, we identified ASTU-045 as a novel, selective METTL3 inhibitor with high efficacy in the MC38 syngeneic model.