METTL1-WDR4-IN-1 TFA

METTL1-WDR4-IN-1 (Compound 1) TFA is a selective competitive inhibitor of the methyltransferase complex METTL1-WDR4 ( IC₅₀ =144 μM). METTL1-WDR4-IN-1 TFA inhibits the m 7 G methyltransferase activity of the METTL1-WDR4 complex, blocking the m 7 G modification of PKM mRNA, reducing PKM2 protein expression, disrupting the METTL1/PKM2/H3K9la positive feedback loop, and simultaneously inhibiting PKM2 nuclear translocation-mediated CD155 transcriptional activation. METTL1-WDR4-IN-1 TFA can inhibit tumor cell proliferation, weaken glycolytic metabolism, reverse tumor immune evasion (restoring NK cell and CD8 + T cell function), and regulate RNA epigenetic modification and the tumor immune microenvironment. METTL1-WDR4-IN-1 TFA can be used in immunotherapy research for cancers such as colorectal cancer, and is particularly suitable for use in combination with PKM2 inhibitors to enhance anti-tumor treatment efficacy ^{[1] [2]}.

In Vitro, METTL1-WDR4-IN-1 TFA, as a METTL1 inhibitor, downregulates METTL1 protein and mRNA expression in HCT-116 and RKO CRC cells, inhibits m7G modification of PKM mRNA, and reduces PKM2 protein levels^[2]. METTL1-WDR4-IN-1 TFA inhibits glycolysis in CRC cells, reducing extracellular acidification rate (ECAR) and lactate accumulation, and downregulating H3K9la histone modification levels^[2]. METTL1-WDR4-IN-1 TFA inhibits PKM2 nuclear translocation in CRC cells, reduces CD155 transcription and protein expression, and enhances the expression of NK cell activation-related markers CD107a and CD16^[2]. METTL1-WDR4-IN-1 TFA, in combination with the PKM2 inhibitor Shikonin, synergistically downregulates PKM2, H3K9la, and CD155 expression in CRC cells and synergistically inhibits cell proliferation^[2].

References:
[1]. Francesco Nai, et al. Small-Molecule Inhibitors of the m7G-RNA Writer METTL1. ACS Bio Med Chem Au 2023, Publication Date:December 12, 2023