METTL1, in complex with its partner protein WDR4, is the principal writer of internal and RNA-associated N7-methylguanosine (m7G), an epitranscriptomic modification that remodels translation, RNA stability, and stress-response pathways. Across diverse cancer types, including hepatocellular carcinoma, cholangiocarcinoma, lung and bladder cancer, glioma, AML, and prostate cancer, METTL1/WDR4-driven expansion of m7G-modified tRNAs and stabilization of codon-biased mRNAs amplifies oncogenic programs governing cell-cycle progression, EMT, DNA repair, and immune evasion. Context-specific roles extend to autoimmune, cardiovascular, and neurological disorders, where METTL1 regulates hypertrophy, fibrosis, angiogenesis, neurodevelopment, and inflammation. Recent advances have established METTL1 as a tractable methyltransferase target: fragment-derived SAM-pocket ligands provide optimal starting points, and recently disclosed THIQ-based inhibitors report nanomolar inhibition, robust cellular target engagement, and functional suppression of tRNA m7G in cells. These advances provide the first chemical foothold for therapeutic modulation of m7G pathways and underscore METTL1 as a promising yet complex target requiring careful biological stratification.
Emanuele Fabbrizi, Gebremedhin S Hailu, Andrea Mancini et al.· Journal of Medicinal Chemist...· 0 citations
The convergence of oxidative stress and inflammation drives neurodegeneration and cancer, positioning NADPH oxidases (NOXs) as critical therapeutic targets. Starting from the polyfunctional thiadiazolopyrimidine hit 1, we systematically truncated its peripheral arms to map minimum pharmacophoric requirements. While extensive clipping compromised activity, strategic optimization yielded the streamlined analogue 5. In silico, 5 acted as a competitive NADPH mimic; in cell-free assays, it maintained multi-isoform potency, inhibiting NOX1 and NOX5 at low-micromolar concentrations. In rat brain subcellular fractions, 1 and 5 demonstrated concentration-dependent neuroprotective and antioxidant efficacy (1–10 μM) by suppressing lipid peroxidation and preserving mitochondrial and synaptosomal viability. Notably, chemical profiling proved that 5 successfully stripped away the pro-oxidant liabilities and radical-scavenging artifacts inherent to 1. In cancer, 1 displayed some antiproliferative activity, mainly in hematological malignancies. Compound 5, although aqueous solubility issues limited its cellular antiproliferative performance, represents a specific, artifact-free architectural starting point for future selective NOX inhibitor development.
Emanuele Fabbrizi, Andrea Mancini, Chiara Lambona et al.· ACS Medicinal Chemistry Lett...· 0 citations
