WDR5 (WD Repeat Domain 5)

The inhibition of OPN increased GBM sensitivity to temozolomide (TMZ) in orthotopic models. This study revealed the potential mechanism by which hypoxia-induced OPN+ GAMs promote the mesenchymal transition in GBM cells and demonstrated the therapeutic potential of targeting OPN to enhance TMZ treatment effectiveness.

These findings reveal unexpected conformational adaptability of the WIN site and demonstrate that its recognition capacity extends beyond the canonical mode defined by histone H3 and other partner proteins. Collectively, our results expand the structural repertoire of WIN-site recognition and establish a framework for rational design of next-generation WDR5 inhibitors that exploit multi-site engagement and alternative binding topologies.

Our study establishes a robust and scalable method that integrates single-cell spheroids with proteomics to model and quantify ITH in CRC. By capturing clinically relevant diversity across morphology, viability, proteomic profiles and drug response, this approach provides a foundation for translating spheroid- and proteomics-based assays into personalized therapeutic testing.

Pharmacological inhibition of the WDR5-NANOG interaction suppresses leukemia stem cell expansion in vivo, highlighting its therapeutic potential. Collectively, this study reveals that WDR5-dependent regulation of NANOG condensate dynamics links phase-separated assemblies to transcriptional control of stem cell identity in physiological and pathological contexts.

While taxanes such as docetaxel (Dtx) and cabazitaxel (Cbz) are widely employed, therapeutic resistance remains a major clinical obstacle...Moreover, combination treatment with the mTOR inhibitor Torin-1 and docetaxel synergistically enhanced therapeutic response in Menin-depleted resistant cells. MEN1 knockdown also abrogated tumor growth in vivo.These findings identify Menin as one of the key mediator of taxane resistance in CRPC through the regulation of mTOR. Targeting Menin, alone or in combination with mTOR inhibition, represents a promising strategy to overcome resistance and improve therapeutic outcomes in taxane-refractory PC.

Conclusively, the findings indicate that histone methylation-driven TRMT6 is crucial for the translation of FTH1 and FTL, which bridges the understanding of m1A tRNA modification and ferroptosis. These results highlight TRMT6 as a novel potential therapeutic target for TNBC.

In this issue of Cell Chemical Biology, Zhang et al.1 report the identification of a high-affinity EMBOW-derived inhibitor of WDR5, Ac7, which demonstrates in-cell target engagement and in vivo antileukemic efficacy. The microprotein-inspired inhibitor potently blocks the WDR5-MLL1 interaction, suppressing H3K4 methylation and transcription of target genes in mixed lineage leukemia (MLL)-rearranged leukemia.

Together, these results establish a first evaluation of BindCraft for peptide binder prediction. Despite remaining limitations, this tool shows the potential to rival display technologies in delivering high-affinity ligands for therapeutic development.

This study demonstrated that PRDM15 in GC cells could recruits the histone methyltransferase complex PRMT5/Mep50/WDR5 to promote PVR transcription, thereby activating the PVR/TIGIT axis, which inhibits TRM cells activation and mediates immune escape and GC progression.

Molecular docking studies demonstrated favorable binding affinities of FDA-approved HCC drugs (sorafenib, lenvatinib, and regorafenib) to these binding pockets, suggesting an off-target mechanism by which these drugs might influence mitochondrial function through the hsa-miR-138-5p pathway. These findings contribute to the growing understanding of miRNA-mediated regulation in HCC and offer a foundation for developing novel microRNA-targeting drugs to modulate mitochondrial dynamics to manage HCC progression.

Importantly, in xenograft mouse models, Ac7 demonstrated significant anti-tumor activity with low toxicity. This work offers a promising strategy for targeting epigenetic regulators with peptide-based therapeutics, providing a foundation for innovative treatments in leukemia.

Thus, this study profiles the molecular alterations that occur during WDR5-MLL1 complex inhibition, offering crucial mechanistic insights that establish a solid framework for developing targeted treatments for MLL-rearranged leukemia. The distinctive binding characteristics and conformational dynamics exhibited by the identified compounds provide a compelling foundation for future experimental approaches to leukemia intervention.