Abstract 5122: Regulating m6A-RNA modification as new therapies for cancer

Abstract The role of post-transcriptional modifications of mRNA in regulation of gene expression, stem-cell maintenance, and differentiation has gained significant interest. Transcriptome-wide mapping has revealed that the most abundant internal mRNA modification is the N6-methyladenosine (m6A), which is present in > 25% of all mRNAs. The N6-methylation of adenosine is a reversible modification controlled by a multiprotein complex comprised primarily of METTL3 and METTL14, which is responsible for the methylation step, and by two Fe(II)-α-ketoglutarate-dependent dioxygenases, ALKBH5 and FTO, which drive the reverse, demethylation step. In addition, FTO, but not ALKBH5, is responsible for the demethylation of N6, 2’-O-dimethyladenosine (m6Am), a prevalent modification frequently found at the 5′ cap-adjacent adenosine of mRNA where it plays a critical role in controlling mRNA stability and translation. In GBM, reduced levels of m6A and m6Am are involved in cell proliferation, survival, and differentiation. As such pathways are known to be directly linked to acquisition of stem-like cell properties in GBM and other solid and hematological tumors, m6A dysregulation is believed to play a role in the generation of stem-like tumor initiating cells and tumorigenesis where such properties are known to be important for tumor progression, recurrence, and resistance. In GSCs, knockdown of the m6A demethylases FTO and its homolog ALKBH5 suppresses GSC-induced tumorigenesis. Moreover, FTO inhibition prolongs lifespan in tumor bearing mice. Recently, we identified novel inhibitors of FTO that impaired sphere formation of GSCs in 3D organoid models in a manner comparable to FTO silencing. Further medicinal chemistry efforts in this area led to the discovery of a novel series of drug-like small molecules, exemplified by the oxetane derivative FTO-43N that selectively inhibit FTO over ALKBH5. These molecules act as competitive inhibitors of FTO and demonstrate potent antiproliferative effects in glioblastoma. These promising results indicate that selective inhibition of FTO could be an effective strategy to target the resistant stem-cell populations in GBM. Furthermore, assessment of in vitro safety pharmacology (CEREP SafetyScan) and brain/plasma PK suggest that FTO-43N and related compounds are an attractive selective FTO inhibitors as drug candidates for the treatment of GBM. Accordingly, using structure-based design strategies combined with advanced in vitro and in vivo modeling systems, lead-optimization studies to identify candidate FTO inhibitors with pharmacokinetic (PK), in vivo efficacy, and safety/tolerability profiles suitable for further drug development. Citation Format: Tariq Rana. Regulating m6A-RNA modification as new therapies for cancer [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 5122.