Jul 2026· Journal of Medicinal Chemistry· Vol 69, pp. 17736 - 17769· 0 citations· 131 references
Medicine
TL;DR
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.
Abstract
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.
This review critically synthesizes the multifaceted roles of RNA modifications to bridge the gap between descriptive epitranscriptomic mapping and functional tumor biology, and aims to facilitate the translation of epitranscriptomic findings into clinical applications.
Epitranscriptomic regulation has emerged as a critical mechanism in cancer biology, particularly in the development of chemoresistance. RNA modifications including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), 7-methylguanosine (m7G), pseudouridine (Ψ), and A-to-I editing dynamically control mRNA stability, splicing, translation, and degradation. RNA-modifying proteins called 'writers,' 'erasers,' and 'readers' regulate post-transcriptional networks to enable tumor adaptation and chemoresistance. In platinum-resistant tumors, epitranscriptomic changes modulate DNA damage response, apoptosis, drug efflux, and detoxification pathways. Preclinical studies demonstrate that pharmacological inhibition of key regulators, such as METTL3 inhibitors (STC-15, STM2457, UZH2) or FTO inhibitors, can sensitize tumors to platinum drugs and stimulate anti-tumor immunity. However, clinical translation remains limited by off-target effects, toxicity, and highly context-specific responses. Epitranscriptomic profiling may help identify novel biomarkers and guiding precision strategies to overcome chemoresistance.
P. Harvanik, T. Hudáková, M. Šemeláková et al.· Advances in Medical Sciences· 1 citation
Coactivator-associated arginine methyltransferase 1 (CARM1/PRMT4) is a signal-responsive epigenetic regulator that couples oncogenic and stress signals to chromatin, transcription, RNA processing, metabolism, and genome maintenance. Its effects arise from both asymmetric arginine methylation of histone and non-histone substrates and methyltransferase-independent scaffolding activities. This review critically synthesizes the structural basis, substrate networks, methylarginine readers, and cancer-contextual functions of CARM1. We propose that its apparently opposing oncogenic and tumor-suppressive activities are determined by lineage-specific substrates, regulatory post-translational modifications, cofactor and chromatin availability, and stage- or microenvironment-dependent stress signals. We further evaluate CARM1-directed therapy using an evidence-graded framework. Catalytic inhibitors such as TP-064 and EZM2302 differ in binding mode and substrate coverage, whereas emerging degraders can remove scaffolding functions but remain constrained by delivery, E3-ligase heterogeneity, pharmacokinetics, and therapeutic-window uncertainties. Biomarker-guided synthetic-lethal and immunotherapy combinations may therefore offer the most tractable route to clinical translation. This framework positions CARM1 as a context-conditioned signal-to-chromatin translator rather than a uniformly druggable oncogene.
Lu-Yao Zhu, Ya-Jie Liang, Qi-Qi Mao et al.· Biochimica et biophysica act...· 0 citations
This review systematically synthesizes current knowledge regarding the multifaceted roles of YTHDC2 in disease progression, prognosis, and therapy, offering a comprehensive framework to guide future investigations.
Yan-Ying Hu, Qi Zhou, Ning Xu et al.· Cells· 0 citations
Loss of methylthioadenosine phosphorylase (MTAP), which occurs in approximately 10-15% of non-small-cell lung cancers and other solid tumors, represents a key synthetic-lethal vulnerability linking tumor metabolism to epigenetic regulation. MTAP deletion disrupts the methionine salvage pathway, leading to accumulation of methylthioadenosine (MTA) and selective dependence on protein arginine methyltransferase 5 (PRMT5). This metabolic rewiring provides a unique therapeutic opportunity to target the MAT2A-PRMT5 axis. This review summarizes recent advances in understanding MTAP biology, including the PRMT5/MAT2A feedback network, tumor heterogeneity, and adaptive resistance mechanisms encompassing metabolic compensation, splicing plasticity, and immune-cold microenvironments associated with 9p21 co-deletion. Emerging clinical data on MTA-cooperative PRMT5 inhibitors and MAT2A inhibitors are discussed, alongside challenges in diagnostic accuracy, biomarker validation, and patient stratification. Despite encouraging early-phase activity, the translation of MTAP-directed therapy is constrained by diagnostic discordance, tumor adaptability, and the absence of prospective, biomarker-driven trials. Future progress will depend on harmonized detection methods, integration of metabolic biomarkers, and rational therapeutic combinations with targeted or immune-based approaches. Collectively, targeting the MTAP-MAT2A-PRMT5 axis exemplifies a metabolism-informed precision-oncology strategy with significant translational potential.
Z. Arter, Joo Sung Shim, C. Park et al.· Cancer Treatment Reviews· 0 citations
It is argued that while epitranscriptomics represents a compelling regulatory axis in cancer cell death, advancing the field will require integrative, high-resolution, and functionally precise approaches to move beyond correlative frameworks toward mechanistic and clinically actionable insights.
A. Mukherjee, Ankit Kumar Bharti, D. Mathew et al.· Functional & Integrative Gen...· 0 citations
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