Research Projects

The dysregulation of N6-methyladenosine (m⁶A) drives an aberrant transcription, and translation programs that lead to the formation of cancers. The m⁶A modification is mediated by its methyltransferase (writers), demethylase (erasers), and recognition (readers). Amongst all YTH family proteins, YTHDF2 is identified as an m⁶A reader protein and has been mainly studied for its function in affecting mRNA stability and translation efficiency. The overexpression of YTHDF2 forms several types of cancers and associated with mutation, microsatellite instability, and mismatch repair. The YTHDF2 protein inhibition also triggers apoptosis in triple-negative breast cancer. The METTL3 protein facilitates the substrate mRNA recognition and binding and an attractive target for studying potential inhibitors. METTL3 influences T-cell differentiation and immune cell development, and its inhibition has been shown to boost immune responses. Meanwhile, YTHDF2 stabilizes PD-L1 mRNA, helping tumors evade immune detection. Targeting both METTL3 and YTHDF2 can enhance T-cell activity and improve the efficacy of ICBs (immune checkpoint inhibitors). The critical oncogenes, such as YTHDF2 and METTL3, play a pivotal role in ATP synthesis and immune evasion, thereby driving disease progression and resistance to CAR-T therapy. The development of selective inhibitors can suppress B-cell malignancies and enhance sensitivity to CAR-T therapy, offering a transformative avenue for therapeutics. Despite having significant relevance, limited small-molecule inhibitors with moderate efficacies are available, hence presenting substantial research gaps. Targeting m⁶A modification remained challenging because the expected “on-target, off-tumor” activity may potentially lead to significant toxicity. Hence, understanding this counterintuitive concept can aid in the design of small molecules with new chemotypes to elucidate m⁶A recognition, which is highly desired. Encouraged by the above facts, we proposed to discover first-in-class dual inhibitors against METTL3 and YTHDF2 oncogenes through virtual screening of diverse chemotypes and biological evaluation studies.