Abstract N6-methyladenosine (m6A) 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 m6A methyltransferase complex, is primarily responsible for depositing m6A 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 (m6A 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. Citation Format: Laurence Mévellec, Nicolas George, Ludovic Waeckel, Rémi Longuespée, Nathalie Weidner, Hugues Prevet, Céline Ronin, Jean-Michel Linget, Anna Bonhoure, Roland Blanqué, Sabine Gratzer. ASTU-045, a novel METTL3 inhibitor with anti-tumor activity in the MC38 syngeneic mouse model abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4485.
Mévellec et al. (Fri,) studied this question.