J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42400372
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EGFR L858R is an activating mutation associated with aberrant EGFR signalling, and molecules capable of recognising this mutant remain of research interest. In this study, a virtual peptide library containing 59 319 hept...EGFR L858R is an activating mutation associated with aberrant EGFR signalling, and molecules capable of recognising this mutant remain of research interest. In this study, a virtual peptide library containing 59 319 heptapeptides was screened against the EGFR L858R crystal structure, leading to the identification of four peptides with favourable predicted binding ability. Among them, Peptide-1 showed the strongest binding affinity in MST assays ( = 0.35 ± 0.02 μM), with higher affinity than the reference peptide DTP-1. Integrated structural and dynamic analyses showed that Peptide-1 could form a relatively stable binding conformation with EGFR L858R. Peptide-1 reduced the viability of SKOV3, OVCAR3, and CaOV3 cells, showed weaker effects on IOSE-80 cells, and its activity was markedly attenuated after EGFR-targeting shRNA transduction. In addition, Peptide-1 decreased Cyclin D1 mRNA expression and increased Caspase-3 mRNA expression. These findings indicate that Peptide-1 can be further investigated as an EGFR L858R-targeting peptide.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42390922
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PDE5 is a subfamily member of the phosphodiesterase (PDE) superfamily. It is encoded by a single PDE5A gene, and its primary function is to specifically hydrolyse cyclic guanosine monophosphate. To date, a few inhibitors...PDE5 is a subfamily member of the phosphodiesterase (PDE) superfamily. It is encoded by a single PDE5A gene, and its primary function is to specifically hydrolyse cyclic guanosine monophosphate. To date, a few inhibitors targeting PDE5, exemplified by sildenafil, tadalafil, and vardenafil, have been approved for the treatment of several diseases including pulmonary arterial hypertension and erectile dysfunction. However, due to their low subtype selectivity, the currently marketed PDE5 inhibitors cause some severe adverse effects in clinical applications, including headaches and visual disturbances. Therefore, discovering new PDE5 inhibitors featuring novel scaffolds and high subtype selectivity for disease treatment and target research remains to attract significant interest from both academics and industry. This review emphasises the rational design, advantages, and potential limitations of PDE5 inhibitors with diverse scaffolds, aiming to generate insights into the discovery and development of novel subtype-selective PDE5 inhibitors.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42377217
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The tumour necrosis factor receptor superfamily (TNFRSF) represents a pivotal signalling network that orchestrates immune homeostasis and regulates cell fate decisions. Lymphotoxin β receptor (LTβR, TNFRSF3), a key TNFRS...The tumour necrosis factor receptor superfamily (TNFRSF) represents a pivotal signalling network that orchestrates immune homeostasis and regulates cell fate decisions. Lymphotoxin β receptor (LTβR, TNFRSF3), a key TNFRSF member, is predominantly expressed on stromal cells and distinct myeloid subsets. Upon binding to its ligands lymphotoxin α1β2 (LTα1β2) and TNFSF14 (LIGHT), LTβR activates multiple signalling cascades, including canonical and non-canonical NF-κB pathways, thereby playing an essential role in tumour immune regulation. LTβR exerts multifaceted functions in lymphoid organogenesis, chronic inflammation, and tumour microenvironment (TME) remodelling. Notably, it promotes the formation of high endothelial venules and tertiary lymphoid structures, facilitating immune cell recruitment and spatial organisation to shape anti-tumour immunity. Recent studies highlight that LTβR agonists show promising therapeutic potential, particularly in combination with immune checkpoint blockade. This review summarises the biological features of LTβR and its dual regulatory roles in the TME, underscoring its potential as a novel target for cancer immunotherapy.
Lu WJ, Ojha R, Rana M
… +3 more, Gautam V, Li JY, Wang SA
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42360103
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Inflammation is a finely tuned host defense mechanism whose perpetual activation is a driver, promoter, and supporter of carcinogenesis. Key mediators of chronic inflammatory processes, NF-kB, JAK-STAT, inflammasomes, r...Inflammation is a finely tuned host defense mechanism whose perpetual activation is a driver, promoter, and supporter of carcinogenesis. Key mediators of chronic inflammatory processes, NF-kB, JAK-STAT, inflammasomes, reactive oxygen species (ROS), and cytokine network, if left unanswered, foster the tumour-supportive environment. Within the tumour microenvironment (TME), inflammatory cells, in combination with stromal and cancerous cells, modulate these pathways and regulate critical tumour hallmarks. Therefore, efforts have been made to understand and tackle the interface between the inflammation-cancer axis, but therapeutic outcomes remain limited. In this context, integrating systems-level biological insights with precision-driven medicinal chemistry may pave the way towards next-generation anti-inflammatory chemotherapeutics. The current review underlines the critical involvement of inflammation in cancer development by providing a comprehensive overview of key molecular pathways. A special emphasis was placed on understanding the medicinal chemistry campaign over the last 5 years for the development of inflammation-targeting small-molecule therapeutics in cancer.
Yuan L, Wang T, Song Y
… +5 more, Guo P, Zhu Y, Cao Y, Song B, Yu Z
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42347745
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Macrophages are plastic innate immune cells that polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes in response to microenvironmental signals, with their dynamic balance governing inflammation resolutio...Macrophages are plastic innate immune cells that polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes in response to microenvironmental signals, with their dynamic balance governing inflammation resolution and tissue homeostasis. This polarization entails profound metabolic reprogramming, wherein ATP-citrate lyase (ACLY) acts as a key regulator. By controlling intracellular acetyl-CoA production, ACLY modulates histone acetylation and chromatin remodeling, thereby influencing the expression of inflammation-related genes. This review systematically outlines ACLY's structural features and elucidates its core mechanisms that integrate metabolic and epigenetic cues to orchestrate macrophage polarization and inflammatory responses. In addition, it summarizes the pharmacological properties and clinical translational potential of ACLY inhibitors, highlighting their promise as therapeutic agents. Collectively, this work aims to offer novel theoretical insights and intervention strategies for targeting macrophage immunometabolism in chronic inflammation and associated metabolic disorders.
Cheng M, Tian Y, Shang J
… +10 more, He W, Zheng Y, Yan C, Chen X, Li J, Jiang Y, Fu Q, Deng X, Xiao X, Song M
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42343149
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To combat antimicrobial resistance (AMR), a novel series of pyrrolo[3,2-]quinazoline-diamine (PQD) derivatives () featuring a flexible benzyl-oxo-benzyl side chain were designed and synthesised via structural optimisatio...To combat antimicrobial resistance (AMR), a novel series of pyrrolo[3,2-]quinazoline-diamine (PQD) derivatives () featuring a flexible benzyl-oxo-benzyl side chain were designed and synthesised via structural optimisation of lead compound IRS-16. All compounds exhibited potent dihydrofolate reductase (DHFR) inhibition. Compound was most notable, showing exceptional enzymatic inhibition (IC = 0.92 nM), surpassing both IRS-16 and trimethoprim. demonstrated broad-spectrum antibacterial activity against Gram-positive (e.g., ) and Gram-negative strains (e.g., ), as well as clinical isolates of , and uropathogenic (UPEC), with MIC values as low as 0.5 μg/mL. It displayed rapid bactericidal action, low resistance propensity, and inhibited biofilm formation by >90% at 0.5 μg/mL. Additional mechanisms included disruption of bacterial membrane integrity, causing leakage of cellular contents. These results identify as a promising lead for developing novel, broad-spectrum DHFR inhibitors with a low resistance risk.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42332952
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Nanozymes-nanomaterials with intrinsic enzyme-like activity-have emerged as a transformative paradigm in biomedicine. Their catalytic proficiency is fundamentally dictated by unique nanoscale characteristics, particularl...Nanozymes-nanomaterials with intrinsic enzyme-like activity-have emerged as a transformative paradigm in biomedicine. Their catalytic proficiency is fundamentally dictated by unique nanoscale characteristics, particularly tuneable surface defects and geometric configurations. This review critically re-evaluates nanozyme catalytic mechanisms, precisely categorising them into reactive oxygen species (ROS)-generating pathways and electron-transfer processes. We highlight recent structural breakthroughs, emphasising the evolution from conventional nanoparticles to single-atom and dual-atom nanozymes (SANs/DANs) that exhibit unprecedented reaction kinetics. Furthermore, we synthesise their advanced applications across in vitro diagnostics, synergistic tumour therapy, antibacterial interventions, and regenerative medicine. Finally, we address current clinical translational bottlenecks and envision how artificial intelligence (AI)-guided rational design will shape the field's future. By bridging fundamental physical chemistry with clinical utility, this review provides a definitive mechanistic roadmap for deploying nanozymes in precision nanomedicine.
Xu W, Zhang Y, Xu Q
… +3 more, Zhao H, Cui L, Wang C
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42306850
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Tubulin, the fundamental component of microtubules, remains a critical target in anticancer therapy. The development of small-molecule tubulin polymerization inhibitors continues to drive the discovery of novel chemother...Tubulin, the fundamental component of microtubules, remains a critical target in anticancer therapy. The development of small-molecule tubulin polymerization inhibitors continues to drive the discovery of novel chemotherapeutic agents. Through systematic analysis of known tubulin inhibitors and in silico binding pocket models, a focused series of 6-aryl-3-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine derivatives was rationally designed and synthesized. Compound 8o exhibited superior antiproliferative potency, with IC₅。 values of 0.050-0.078 µM against HeLa, HCT116, and MCF-7 cancer cell lines. Mechanistic investigations confirmed that 8o effectively inhibits tubulin polymerization, disrupts the microtubule cytoskeleton, induces G₂/M phase arrest, and triggers apoptosis. Preliminary physicochemical assessment indicated that 8o adheres to Lipinski's rule of five, supporting favorable drug-likeness. Collectively, these findings identify 8o as a potent, drug-like colchicine-site tubulin inhibitor with compelling anticancer efficacy, meriting further investigation as a promising lead compound.
Chen C, Chen X, Huang X
… +4 more, Xie Y, Shi P, Qian S, Chen Z
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42295078
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Shikonin, a natural compound, exhibits antitumor effects in DLBCL, but its mechanism remains unclear. Shikonin's cytotoxicity in DLBCL cells was assessed by MTT assays. Ferroptosis and lipid peroxidation markers were ana...Shikonin, a natural compound, exhibits antitumor effects in DLBCL, but its mechanism remains unclear. Shikonin's cytotoxicity in DLBCL cells was assessed by MTT assays. Ferroptosis and lipid peroxidation markers were analysed flow cytometry and biochemical kits. Mechanisms were explored using gene knockdown/overexpression, dual-luciferase assays, RNA pull-down, proteomics, RIP, FISH, and ChIP. Key proteins and genes involved in ferritinophagy and ferroptosis were examined by Western blot, RT-qPCR, and immunofluorescence, with findings validated in a nude mouse xenograft model. Shikonin triggers ferritinophagy and ferroptosis by increasing iron accumulation and lipid peroxidation. LncRNA ADPGK-AS1 protects against ferroptosis by regulating MT2A eIF4G1 interaction. Shikonin triggers ferritinophagy and ferroptosis by disrupting iron metabolism and redox balance. The eIF4G1-ADPGK-AS1/MT2A axis mitigates these effects, revealing shikonin's antitumor mechanism and therapeutic potential.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42274165
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Despite the clinical relevance of KRAS in colorectal cancer, KRAS-specific inhibitors remain limited. Through structure-based virtual screening of a 59,319-member peptide library, we identified four KRAS-targeting peptid...Despite the clinical relevance of KRAS in colorectal cancer, KRAS-specific inhibitors remain limited. Through structure-based virtual screening of a 59,319-member peptide library, we identified four KRAS-targeting peptides, among which Peptide-1 showed the most favourable docking profile. MST assays confirmed Peptide-1 had the highest affinity among Peptides 1-4, with stronger binding to KRAS than to other KRAS mutants. Structural analysis, molecular dynamics simulations, and free-energy calculations indicated that Peptide-1 formed a stable and energetically favourable complex with KRAS through extensive hydrogen bonding and hydrophobic interactions. Peptide-1 showed favourable human serum stability and cellular NanoBRET-supported engagement with KRAS. Functionally, Peptide-1 displayed potent antiproliferative activity in colorectal cancer cell lines, weaker effects on normal cells and reduced efficacy after KRAS knockdown. In SW480 cells, Peptide-1 was associated with reduced ERK1/2 phosphorylation, p21 upregulation, and G0/G1 accumulation. Overall, these findings support further investigation of Peptide-1 as a KRAS-targeting peptide for colorectal cancer drug discovery.
Lin TC, Wu ZS, Huang SM
… +3 more, Liu CW, Hu JM, Wen CC
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42253188
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Targeted therapies have broadened the treatment landscape for colorectal cancer (CRC), highlighting the need for rational combination strategies. Although sorafenib and GW5074 show therapeutic promise and lidocaine may s...Targeted therapies have broadened the treatment landscape for colorectal cancer (CRC), highlighting the need for rational combination strategies. Although sorafenib and GW5074 show therapeutic promise and lidocaine may sensitise cancer cells to treatment, the mechanisms underlying these combinations remain poorly understood. Here, we systematically evaluated the effects of combining lidocaine with sorafenib and/or GW5074 in CRC cell lines. Combination index analysis showed that sorafenib increased responsiveness to GW5074 by 19.5- and 1.7 × 10-fold in HT29 and SW480 cells, respectively, while lidocaine enhanced this response by 45- and 3 × 10-fold. Ropivacaine, bupivacaine, and levobupivacaine also showed synergistic interactions with GW5074 by 14- and 1.03 × 10-fold, 15.1- and 6.5 × 10-fold, and 33.6- and 3.8 × 10-fold in HT29 and SW480 cells, respectively. Lidocaine and ropivacaine in combination with sorafenib exhibited an antagonistic effect in HT29 cells, others were synergistic effects. These combinations modulated cell-cycle progression, activated cell death pathways, and amplified cellular stress responses in a context-dependent manner.
Feng Y, Li T, Chen C
… +5 more, Tang Z, Liu Z, Gu C, Pan Y, Chen J
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42240360
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The natural alkaloid reticuline exhibits promising anti-inflammatory activity in preclinical models; however, its development is hindered by moderate potency and limited accessibility. To overcome these hurdles, we devel...The natural alkaloid reticuline exhibits promising anti-inflammatory activity in preclinical models; however, its development is hindered by moderate potency and limited accessibility. To overcome these hurdles, we developed an efficient synthetic route to reticuline, enabling the design and synthesis of 21 structural analogues. Through systematic structure-activity relationship (SAR) exploration, compound was identified as a lead candidate, demonstrating potent anti-inflammatory effects coupled with low cytotoxicity in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Mechanistic studies revealed that suppressed the production of nitric oxide (NO), reactive oxygen species (ROS), and the pro-inflammatory cytokines TNF- and IL-6. This anti-inflammatory effect was accompanied by the downregulation of iNOS and COX-2 expression and the inhibition of MAPK signalling pathway. Collectively, this work presents as a promising anti-inflammatory lead compound and provides a rational strategy for the structural optimisation of natural product-inspired scaffolds.
Zhang M, Chen J, Liang R
… +8 more, Jiang W, Lin M, Wen S, Liu D, Yi B, Chen R, Chen T, Li Z
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42212521
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Bone Marrow Tyrosine Kinase on Chromosome X (BMX), also known as epithelial/endothelial cell kinase (ETK), is a core member of the Tec family of non-receptor tyrosine kinases. Structurally, BMX kinase contains an N-termi...Bone Marrow Tyrosine Kinase on Chromosome X (BMX), also known as epithelial/endothelial cell kinase (ETK), is a core member of the Tec family of non-receptor tyrosine kinases. Structurally, BMX kinase contains an N-terminal PH domain, a BH domain, a SH2 domain, a SH3 domain and a C-terminal catalytic tyrosine kinase domain. This distinctive modular architecture enables BMX to engage in diverse cellular signalling cascades. It has been reported that BMX is highly expressed and plays an oncogenic role in various cancers. In this paper, we mainly explore the function and mechanism of BMX in tumour cell proliferation, apoptosis, invasion, metastasis, cancer stem cell properties, angiogenesis and drug resistance. Furthermore, the research focus on summarising the research progress of BMX inhibitors for cancer treatment. This review aims to provide a theoretical framework for cancer therapy by targeting BMX.
Anwer KE, Ramadan RM, Nossier ES
… +4 more, Altwaijry NA, Saleh A, Bräse S, Husseiny EM
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42210722
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Utilising drug design methodologies including bioisosteric modification and substituents variation, sets of 4,5,6,7-tetrahydrobenzo[]thiophene carboxamides were synthesised, by conventional heating and eco-friendly micro...Utilising drug design methodologies including bioisosteric modification and substituents variation, sets of 4,5,6,7-tetrahydrobenzo[]thiophene carboxamides were synthesised, by conventional heating and eco-friendly microwave-assisted techniques, as CDK-2 inhibitors. These entities were assessed for their antitumor effects against hepatic HepG-2 and breast MCF-7 and MDA-MB-231 carcinomas, in which dimethoxy and dimethyl-bearing analogues and demonstrated significant cytotoxicity and selectivity against the examined cancer cells. Consequently, they were chosen for further assays to determine their mechanism. The findings suggest that these compounds may exert cytotoxicity by inhibiting CDK-2. Compound displayed the highest CDK-2 inhibition, exceeding roscovitine by nearly threefold. Besides, it arrested the MDA-MB-231 cell cycle at the G0/G1 phase by apoptotic stimulation. Molecular modelling showed strong binding of the bioactive analogues to the active pocket of CDK-2 receptor, suggesting their potential as lead inhibitors.
Pu F, Tao A, Qiu P
… +9 more, Deng W, Chen Z, Cao Z, He Y, Wang PG, Zhang Y, Ning C, Li X, Xu J
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42209292
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CDK7 has emerged as a highly promising anticancer target, as its dual indispensable roles in cell cycle progression and transcriptional regulation for cancer cell proliferation and survival. Herein, we describe the ratio...CDK7 has emerged as a highly promising anticancer target, as its dual indispensable roles in cell cycle progression and transcriptional regulation for cancer cell proliferation and survival. Herein, we describe the rational design and identification of novel tetracyclic CDK7 inhibitors with an azaindole/indole-fused pyrimidine scaffold, achieved via a cyclisation-based conformational restriction strategy. Compound emerged as a potent, highly selective CDK7 inhibitor (IC = 1.9 nM), outperforming clinical candidate SY-5609 (IC = 2.5 nM). It exhibited prominent antiproliferative activity against HCT116 colorectal cancer cells (IC = 1.7 nM) and excellent selectivity over other CDK isoforms. In vivo, exerted robust dose-dependent antitumor efficacy in HCT116 xenograft model without obvious toxicity. Collectively, its superior in vitro potency, high CDK7 selectivity, and significant in vivo antitumor activity highlight the potential of as a chemical tool for investigating CDK7 biology and as a lead compound for further pharmacokinetic optimisation.
Chatterjee J, Joshi G, Jha V
… +6 more, Bhujbal SM, Rathour S, Majumdar S, Wahajuddin M, Bharatam PV, Kumar R
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42179048
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In this study, we report the Pictet-Spengler enabled synthesis of a series of eighteen carboxamide-substituted imidazo[1,2-]quinoxaline derivatives () targeting epidermal growth factor receptor (EGFR) and tubulin. Compou...In this study, we report the Pictet-Spengler enabled synthesis of a series of eighteen carboxamide-substituted imidazo[1,2-]quinoxaline derivatives () targeting epidermal growth factor receptor (EGFR) and tubulin. Compounds and exhibited potent antiproliferative effects against MCF-7 breast cancer cells, with IC values of 4.59 ± 0.23 µM and 4.01 ± 0.14 µM, respectively, outperforming erlotinib (IC = 9.39 ± 0.16 µM). In enzymatic assays, and inhibited wild-type EGFR with IC values of 294.45 nM and 383.90 nM, respectively. Notably, displayed microtubule-stabilising activity comparable to that of paclitaxel and induced ROS generation, mitochondrial membrane depolarisation, and G2/M phase cell cycle arrest. Molecular docking and molecular dynamics simulations confirmed stable binding of compounds at the EGFR ATP-binding site and the tubulin taxol-binding site.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42179005
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Bacterial neuraminidase (BNA) is a potential target for discovering anti-infective agents. Here, the BNA inhibitory activity of the ethanolic extract of (EEPC) was investigated using integrated experimental and computat...Bacterial neuraminidase (BNA) is a potential target for discovering anti-infective agents. Here, the BNA inhibitory activity of the ethanolic extract of (EEPC) was investigated using integrated experimental and computational approaches. Affinity ultrafiltration-UPLC-Q-Orbitrap-MS prioritised 11 representative constituents as putative BNA-interacting compounds. Five compounds () inhibited BNA with IC values of 4.67-34.09 μM. Bakuchiol () exhibited the strongest activity (IC = 4.67 ± 0.26 μM), and compounds , , and were more active than the positive control, quercetin (IC = 13.63 ± 1.05 μM). Kinetic analysis indicated that bakuchiol () was competitive, whereas compounds showed mixed-type inhibition. Docking and molecular dynamics analyses suggested that bakuchiol () and 3-hydroxybakuchiol () may form relatively stable BNA complexes. absorption, distribution, metabolism, excretion, and toxicity analysis further supported bakuchiol () as a promising lead candidate among the tested compounds.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42169673
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Immune checkpoint inhibitors (ICIs) face challenges of drug resistance and immune-related adverse events (irAEs). Traditional Chinese medicine (TCM)-including single herbs, compounds, and active monomers-enhances ICI eff...Immune checkpoint inhibitors (ICIs) face challenges of drug resistance and immune-related adverse events (irAEs). Traditional Chinese medicine (TCM)-including single herbs, compounds, and active monomers-enhances ICI efficacy and reduces toxicity by remodeling the tumor immune microenvironment, regulating gut microbiota, and modulating key immune pathways. TCM also alleviates ICI-induced colitis and myocarditis, demonstrating the value of holistic and syndrome-differentiated therapy. Future research should clarify synergistic mechanisms to advance precise integration of TCM and ICI immunotherapy.
Nannini S, Sieffert C, McGown A
… +18 more, Gao XY, Jarvis A, Kostakis GE, Galvacsi A, Kallay C, Moraru R, Baud MG, Mandel S, Balourdas DI, Joerger AC, Orvain C, Peschard S, Nion A, Mellitzer G, Lottiaux S, Spencer J, Gross I, Gaiddon C
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42163716
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Point mutations in p53 favour tumour aggressivity, particularly in gastric cancer (GC), and offer a target for small molecule-based anticancer treatments. This study focused on the p53-Y220C mutation, which causes p53 mi...Point mutations in p53 favour tumour aggressivity, particularly in gastric cancer (GC), and offer a target for small molecule-based anticancer treatments. This study focused on the p53-Y220C mutation, which causes p53 misfolding due to thermal instability associated with the creation of a pocket that may accommodate small molecules. This mutation also creates an additional free cysteine thiol group that may react with Michael acceptors. Using an integrated and approach, four compounds (AG1, AG2, AG3, and RK349) were screened for potential reactivation of p53-Y220C in GC cells. AG3, a compound with zinc chelation and Michael acceptor properties, was found to induce p53 target gene expression via p53-dependent and -independent pathways. AG3 limited reactive oxygen species production, reducing toxicity to healthy cells. Furthermore, AG3 induced p53-dependent cytotoxicity and enhanced chemotherapy response. This study presents a novel compound with p53-Y220C reactivation potential, highlighting its promise for further development.
Chang HL, Fang CH, Chang HL
… +8 more, Lee YF, Hsu WL, Chang JH, Chien MH, Goodman SD, Chang SY, Fang WH, Su KY
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42117622
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Cadmium is a pervasive environmental carcinogen known to disrupt multiple DNA repair pathways, yet its direct impact on uracil base excision repair enzyme activity remains unclear. Here, we quantitatively demonstrate tha...Cadmium is a pervasive environmental carcinogen known to disrupt multiple DNA repair pathways, yet its direct impact on uracil base excision repair enzyme activity remains unclear. Here, we quantitatively demonstrate that cadmium potently inhibits hSMUG1, a key enzyme initiating removal of mutagenic U:G mispairs arising from cytosine deamination. Using a nucleotide-resolution MALDI-TOF mass spectrometry assay, we show that cadmium suppresses hSMUG1 activity in a dose-dependent manner (IC = 4.6 μM), with near-complete inhibition at concentrations ≥25 μM. Notably, five Ganoderma lucidum extracts derived from different strains and extraction methods restored hSMUG1 activity (16.4-21.6%) under cadmium stress. ICP mass spectrometry revealed that these extracts reduced cadmium ion levels by 40-73%, suggesting metal chelation as a contributing mechanism. Together, our findings uncover a previously unrecognised mechanism by which cadmium compromises base excision repair and establishes a robust framework for evaluating environmental metal toxicity and its modulation at single-nucleotide resolution.