Histone post-translational modifications regulate gene expression, yet linking specific marks to their regulatory enzymes remains challenging. Douglas and Seath review chemical biology strategies—spanning synthetic peptides, semisynthetic nucleosomes, and intact chromatin—that systematically map PTM-dependent interactions, highlighting how increasing biological complexity advances functional understanding of the histone code.
Sato et al. determine high resolution structures of the human herpesvirus 1 helicase primase complex (HPC), revealing how clinical inhibitors allosterically inactivate the HPC. Their findings illuminate α-subfamily drug specificity and offer a structural basis for developing antivirals targeting a wider range of herpesviruses.
Venkataramani et al. identify two potent, ATP-competitive inhibitors of DYRK1A, FC-2 and FC-3, which suppress EGFR-driven glioblastoma (GBM) growth. Inhibitor-resistant mutants confirm DYRK1A as the functional target, highlighting FC-2 and FC-3 as promising therapeutic candidates in EGFR-dependent GBM and other cancers.
Zhu et al. develop a red-light optogenetic tool to enable spatiotemporal control of O-GlcNAcylation at the plasma membrane. They demonstrate that light-induced O-GlcNAcylation inhibits WNK1 biomolecular condensate formation, thereby suppressing the osmosensing pathway. This work provides a versatile platform to precisely manipulate glycosylation and regulate cell signaling.
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Ketelut-Carneiro, Mathur, and Fitzgerald review the mechanisms and regulation of the different gasdermins (GSDMs) in pyroptosis. They provide a comprehensive overview of the role of GSDMs across infectious and inflammatory diseases and cancer, highlighting key unanswered questions and challenges in targeting GSDMs for therapeutic strategies.
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Cell Chemical Biology
Chandra et al. leverage a human dual-cell model of FA and discover cell-type-specific vulnerabilities to frataxin deficiency. A Miro1-binding probe, MR3, modulates FA cell-type-unique molecular signatures and alleviates mitochondrial damage via potential allosteric reshaping of Miro1 protein. Previously unreported Miro1 ligands expand MR3 chemical diversity.
Hinshaw et al. determine the molecular basis for TRIM21 recruitment to the nuclear pore protein NUP98, showing that an induced protein-protein interface drives the potency and selectivity of the molecular glue mechanism.
PPARγ has emerged as a promising target for the treatment of muscle-invasive urothelial carcinoma (MIUC). Stuckey et al. report the discovery of FX-909, a covalent inverse agonist of PPARγ suitable for clinical development and capable of suppressing PPARG-driven growth in xenograft models of MIUC.
Bradbury, Walsh, and Lanyon-Hogg use affinity-based protein profiling to identify SpsB as a target of the SOS-response inhibitor OXF-077 in MRSA. SpsB is then shown to modulate SOS activation and the frequency of resistance emergence to ciprofloxacin.
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Hao et al. report the cryo-EM structure of the human CbA–Sec61 complex to develop photo-controlled and hypoxia-activated prodrugs. This backbone-engineering strategy overcomes the on-target toxicity of Sec61 inhibition by restricting activity to tumor microenvironments, demonstrating potent anti-tumor efficacy in a colon cancer CDX model.
