N Nature Chemical Biology · Nov 21, 2025 SINE compounds activate exportin 1 degradation through an allosteric mechanism Overexpression of exportin 1 (XPO1/CRM1) in cancer cells mislocalizes numerous cancer-related nuclear export cargoes. Covalent selective inhibitors of nuclear export (SINEs), including the cancer drug selinexor, restore proper nuclear localization by blocking XPO1–cargo interaction. These inhibitors also induce XPO1 degradation through the Cullin–RING E3 ligase (CRL) substrate receptor ASB8. Here we present cryo-electron microscopy structures revealing ASB8 binding to a cryptic XPO1 site that is exposed upon SINE conjugation. Unlike typical molecular glue degraders that directly bridge CRLs and substrates, SINEs bind XPO1 independently of ASB8, triggering an allosteric mechanism that enables high-affinity ASB8 recruitment, leading to XPO1 ubiquitination and degradation. ASB8-mediated degradation is also triggered by the endogenous itaconate derivative 4-octyl itaconate, suggesting that synthetic XPO1 inhibitors exploit a native cellular mechanism. This allosteric XPO1 degradation mechanism expands known modes of targeted protein degradation beyond molecular glue degraders and proteolysis-targeting chimeras of CRL4. Cancer therapy Small molecules Structural biology biology
N Nature Chemical Biology · Nov 03, 2025 Mutant p53 protein accumulation is selectively targetable by proximity-inducing drugs TP53mutant cancers are associated with approximately half of cancer deaths. The most common mechanism of p53 inactivation involves missense mutations. Such mutations inTP53result in a robust upregulation of the p53 protein. Here, we demonstrate an induced proximity approach to selectively killTP53mutant cells. This approach uses the increased abundance of p53 protein inTP53mutant cancer cells to concentrate toxic molecules in these cells. We demonstrate this approach with a molecule that binds the Y220C mutant of p53 and concentrates a PLK1 inhibitor in cells harboringTP53Y220Cmutations. The resulting bifunctional molecule promotes formation of a p53Y220C–PLK1 ternary complex, mislocalizes PLK1, inhibits PLK1 activity, elicits selective G2/M arrest and induces apoptosis inTP53Y220Ccells while sparing wild-typeTP53cells. These data exemplify a potentially generalizable framework for targetingTP53missense mutations by leveraging mutant p53 protein abundance to induce cell death, independent of p53’s transcriptional activity. Cancer therapy Cell death Cell signalling Small molecules biology
N Nature Chemical Biology · Oct 31, 2025 Click-code-seq reveals strand biases of DNA oxidation and depurination in human genome DNA modifications drive aging, neurodegeneration, carcinogenesis and chemotherapy drug action. Accurate mapping of diverse DNA modifications with single-nucleotide precision in complex genomes remains challenging. We upgraded click-code-seq, a click-chemistry-aided DNA-modification mapping strategy, to enable its first application for sequencing oxidation and depurination in the human genome. We developed a companion fluorescence assay, click-fluoro-quant, to rapidly quantify common DNA modifications and novel adaptors to minimize false positives and assess modification frequency. We uncovered that endogenous DNA oxidation in a human cell line mirrors cancer mutational signatures linked to oxidative stress. The chemotherapy drug irofulven preferentially induces depurination in ApA dimers and promoters. Notably, oxidized guanines and apurinic sites, both irofulven induced and endogenous, are depleted in gene transcribed strands, with the strand bias increasing with gene expression. This work substantially advances click-code-seq for deciphering the impacts of key modifications in human DNA on cellular physiology and toxicological responses. Bioinformatics Cancer therapy Chemical modification DNA DNA damage and repair biology
N Nature Chemical Biology · Oct 23, 2025 MED1 IDR deacetylation controls stress responsive genes through RNA Pol II recruitment Cells fine-tune gene expression in response to cellular stress, a process critical for tumorigenesis. However, mechanisms governing stress-responsive transcription remain incompletely understood. This study shows that the MED1 subunit of the Mediator coactivator complex is acetylated in its intrinsically disordered region (IDR). Under stress, SIRT1 associates with the super elongation complex to deacetylate MED1 in promoter-proximal regions. The deacetylated (or acetylation-defective mutant) MED1 amplified stress-activated cytoprotective genes and rescued stress-suppressed growth-supportive genes in estrogen-receptor-positive breast cancer (ER+BC) cells. Mechanistically, deacetylated MED1 promotes chromatin incorporation of RNA polymerase II (Pol II) through IDR-mediated interactions. Functionally, ER+BC cells with deacetylated MED1 exhibit faster growth and enhanced stress resistance in culture and in an orthotopic mouse model. These findings advance our understanding of Pol II regulation under cellular stress and potentially suggest therapeutic strategies targeting oncogenic transcription driven by MED1 and Mediator. Cancer Chromatin Post-translational modifications Transcription biology estrogen mouse experiments
N Nature Chemical Biology · Oct 16, 2025 A small molecule targets LIC1 to suppress lung tumor growth by inducing autophagy Small molecules that induce autophagy in specific biological contexts can provide invaluable chemical probes and potential anticancer therapeutics. Here we identified a potent autophagy inducer 3,4-diisobutyryl derivative of auxarthrol A (DAA) from an endophyte-derived small-molecule library. DAA demonstrates notable antitumor efficacy in non-small cell lung cancer (NSCLC) tumor and sensitizes tumors to anti-PD1 immunotherapy. Using a photoaffinity labeling approach, we identified light intermediate chain 1 (LIC1), a subunit of dynein, as the direct target of DAA. We found that LIC1 is overexpressed in NSCLC tumors and correlates with poor survival. Mechanistically, the targeting of LIC1 by DAA markedly disrupts the interactions between LIC1 and stress-sensing effector RuvB-like AAA ATPase 1, which in turn elevates downstream GCN2–eIF2α–ATF4 axis-mediated integrated stress response, ultimately promoting autophagic cell death. Our findings define LIC1 as a novel therapeutic target for NSCLC and highlight the potential of DAA as a promising autophagy inducer for treatment of this disease. Cancer therapy Cell death Cell signalling Natural products Target identification biology
N Nature Chemical Biology · Sep 15, 2025 ELOVL6 activity attenuation induces mutant KRAS degradation KRASis one of the most frequently mutated oncogenes in cancer. Targeting mutant KRAS directly has been challenging because of minor structural changes caused by mutations. Despite recent success in targeting KRAS-G12C, targeted therapy for another hotspot mutant, KRAS-G12V, has not been described. We used CRISPR–Cas9 genome-wide knockout screens to identify genes that specifically modulate mutant KRAS harboring the G12V substitution. Our top hit, a fatty acid elongase (ELOVL6), showed remarkable selectivity in diminishing KRAS-G12V protein expression and aberrant oncogenic signaling associated with mutant KRAS. Our studies reveal that ELOVL6 can be targeted to control the production of phospholipids exploited by KRAS mutants for function-targeted and trigger-targeted degradation of the protein. Our results demonstrate the basis for a first-in-class small-molecule inhibitor to selectively clear KRAS-G12V from cancer cells. Cancer therapy Cell signalling Membrane lipids Screening Cancer CRISPR Drug Development
N Nature Chemical Biology · Aug 26, 2025 Oncometabolite 5-IP7inhibits inositol 5-phosphatase to license E-cadherin endocytosis E-cadherin downregulation is an epithelial–mesenchymal transition hallmark canonically attributed to transcriptional repression. Here we delineate a metabolite-driven endocytic route of E-cadherin downregulation in inflammation-associated colorectal cancer (CRC). Specifically, IP6kinase-2 (IP6K2), a 5-diphosphoinositol pentakisphosphate (5-IP7) synthase upregulated in patients with CRC, is activated via a ROS–Src phosphorylation axis elicited by dextran sulfate sodium (DSS), generating 5-IP7around adherens junction (AJ) to promote E-cadherin endocytosis and the transcriptional activities of β-catenin. Mechanistically, 5-IP7inhibits inositol 5-phosphatases such as OCRL to promote PI(4,5)P2-mediated endocytic adaptor recruitment. Depleting 5-IP7or overexpressing a 5-IP7binding-deficient OCRL mutant confers resistance to DSS-elicited AJ disruption. Intestinal epithelium-specific IP6K2 deletion attenuates DSS-induced colitis/CRC, whereas an IP6K2 isoform-selective inhibitor protects wild-type but not IP6K2−/−mice against DSS insult. Thus, 5-IP7is an oncometabolite whose stimulus-dependent synthesis relieves a PI(4,5)P2dephosphorylation-based endocytic checkpoint, leading to AJ disassembly and protumorigenic β-catenin activation. Targeting IP6K2 could strengthen intestinal epithelial barrier against inflammation and cancer. Cancer Cell signalling Kinases Membrane trafficking Post-translational modifications Cancer Metabolism Mouse Drug Development Cell Biology
N Nature Chemical Biology · Aug 22, 2025 α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers The energy sensor AMP-activated protein kinase (AMPK) promotes tumor cell survival under stress but how to prevent AMPK activation to blunt tumor progression remains unclear. Here we show that the metabolite α-ketoglutarate (α-KG) dictates AMPK translation through a TET–YBX1 axis, which can be exploited to sensitize human cancer cells to energy stress. α-KG-deficient cells fail to activate AMPK under glucose starvation, which elicits cytosolic NADPH depletion and disulfidptosis. Mechanistically, α-KG insufficiency inhibits TET-dependent transcription of YBX1, an RNA-binding protein required for human-specific AMPK protein synthesis. Similarly, α-KG competitors including succinate and itaconate inhibit the YBX1–AMPK axis and sensitize cancer cells to glucose deprivation. Lastly, cotargeting oncogenic YBX1 and GLUT1 creates synthetic lethality and blunts tumor growth in vivo. Together, our findings link α-KG to energy sensing through AMPK translation and propose that targeting α-KG–YBX1-dependent AMPK translation can sensitize human cancer cells to energy stress for treatment. Cancer therapy Kinases Metabolic pathways Transcription Translation Cancer Metabolism Human Drug Development
