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Hepatocellular carcinoma (HCC) has a dismal prognosis with limited therapeutic options, and drug repurposing is a promising anti-HCC strategy. Pyrimethamine (Pyr), an FDA-approved antifolate drug with potential antitumor activity, its molecular mechanism in HCC remains elusive. In this study, in vitro experiments (MTT, colony formation, flow cytometry) confirmed that Pyr dose-dependently inhibited Hep3B and Huh7 cell proliferation, induced DNA damage and G0/G1 cell cycle arrest, and downregulated CCND1 expression. Mechanistically, Pyr upregulated METTL14 to enhance global m6A modification, and METTL14 directly mediated the m6A modification of CCND1 mRNA; the modified CCND1 was specifically recognized by YTHDF2, leading to its mRNA degradation. Bioinformatic and clinical sample analyses verified that METTL14 was downregulated in HCC tissues and acted as a tumor suppressor in vitro. In HCC patient-derived xenograft (PDX) models, Pyr significantly suppressed tumor growth, upregulated METTL14 and YTHDF2 expression, downregulated CCND1, and exhibited no obvious organ toxicity. This study reveals that Pyr exerts anti-HCC activity by activating the METTL14/YTHDF2 axis to induce m6A-dependent CCND1 mRNA degradation and subsequent G0/G1 arrest, uncovers a novel epitranscriptomic mechanism of Pyr, and supports its repurposing as a potential therapeutic agent for HCC.

The mechanistic target of rapamycin (mTOR) sits at the center of several cellular pathways determining cell growth, function, and stress adaptation. Dysregulated mTOR signaling contributes to aging-related diseases and cancer, making mTOR inhibitors an important class of anticancer therapeutics. Likewise, STAT3 is a transcription factor that drives cell proliferation and survival, and its hyperactivation is implicated in many cancers. As a result, STAT3 inhibitors also represent a promising group of anticancer compounds. This study describes the synthesis and characterization of 10 heteroarene derivatives of torkinib, a known mTOR inhibitor. We evaluated these compounds for their mTOR and STAT3 inhibitory activities, growth inhibitory and senolytic effects. A structure-activity relationship (SAR) study and molecular docking analysis were conducted to elucidate key structural features. Notably, torkinib derivative 4k demonstrated potent mTOR inhibition without affecting STAT3 phosphorylation, whereas its analog 4j inhibited phosphorylation of both mTOR and STAT3. Furthermore, compared to compound 4j, compound 4k exhibited cytotoxicity against both proliferating and senescent cells, comparable to torkinib despite its weaker TORC1 inhibition. In conclusion, our findings reveal structural alignments crucial for enhanced mTOR and STAT3 inhibition.

WD40 repeat-containing protein 5 (WDR5) plays a critical role in chromatin-related processes, and its overexpression is associated with poor prognosis in multiple cancers, making it an attractive therapeutic target. Screening of an approved drug library identified zafirlukast (ZAF), an anti-asthmatic agent, as a binder to the WIN site of WDR5, inhibiting the histone methyltransferase activity of the MLL1 complex with an IC50 of 22.96 μM. Structure-based optimization yielded the candidate HLC40, which not only abolished its original CysLT1 receptor antagonism (IC50 > 5 μM) but also exhibited a 30-fold enhancement in MLL1 histone methyltransferase (HMT) inhibitory activity (IC50 = 0.82 μM). Consistent with these findings, HLC40 exhibited potent antiproliferation efficacy (IC50 = 7-8 μM) in AML cells and demonstrated significant efficacy in the MV4-11 xenograft model (TGI = 49.1% @ 30 mg/kg). Collectively, these results highlight that HLC40 is a promising WDR5-targeting candidate with high therapeutic potential for hematologic malignancies.

Anaplastic lymphoma kinase (ALK) serves as a new target for therapy in non-small cell lung cancer (NSCLC) associated with the presence of the ALK fusion gene. This study reports the development of a series of pyrazole-5-carboxamide derivatives C01-C17 based on the lead compound 7 and hit compound A06 obtained through virtual screening, which was identified through fragment-based drug design. After structural optimization, the selected compound C04 exhibits significant anti-proliferative effects against the ALK-overexpressing cell line H2228 (IC50 = 0.10 μM), as well as promising ALK inhibition (9.58 nM). Molecular docking studies suggest that C04 functions as a type I₁/₂ allosteric inhibitor by forming critical interactions within the ATP-binding region and the hydrophobic pocket of ALK. Furthermore, C04 induces apoptosis in H2228 cells in a dose-dependent manner, inhibits colony formation, and suppresses tumor cell migration. These findings provide new insights into the search for novel ALK inhibitors.

KRAS G12D, the most common oncogenic mutation of KRAS, represents a promising therapeutic target for solid tumors. Herein, we report the discovery of 16k, a novel KRAS G12D inhibitor based on a 6-methoxyquinazoline scaffold, identified through the scaffold hopping and structural optimization strategies. The compound 16k exhibited significant antiproliferative effects against KRAS G12D mutant tumor cells, specifically the AGS and GP2D cell lines (IC50 = 0.18 and 0.21 μM, respectively), with minimal cytotoxicity toward normal cells and effectively inhibited colony formation. Preliminary mechanistic investigations revealed that 16k markedly elevated the levels of ROS, disrupted the balance of mitochondria-associated apoptotic proteins, and induced MMP collapse by inhibiting the downstream ERK/AKT signaling pathways of KRAS in AGS and GP2D cells. Molecular dynamics simulations confirmed that 16k binds stably to KRAS G12D, with hydrogen bond interactions observed with residues His 95, Arg 68, and Asp 12, further supporting the consistency of the docking results. 16k also demonstrated favorable drug-like properties, including good hepatic microsomal metabolic stability and a safer toxicity profile in vivo. In conclusion, this work expands the structural diversity of KRAS G12D inhibitors and highlights 16k as a promising lead compound for the development of targeted therapies against G12D-mutant cancers.

In this study, an efficient click synthesis has been employed to combine isatin, Schiff base, and 1,2,3-triazole in a single framework. Propargylation of 5-bromoisatin, followed by condensation with isoniazid, furnished the corresponding isatin-isoniazid hydrazone-based alkyne intermediate. Subsequent CuAAC reaction with a series of aromatic azides afforded a library of 1,2,3-triazole derivatives incorporating isatin-isoniazid hydrazone conjugates. The synthesized click adducts were characterized using the appropriate spectroscopic techniques, including 1H, 13C, and 19F NMR, and HRMS. They were also subjected to dual EGFR/PARP-1 inhibition and cytotoxic screening in MDA-MB-231 TNBC cells, and apoptosis induction was assessed by flow cytometry and RT-PCR. Compounds 9, 10, and 11 exhibited IC50 values of 93, 64, and 78 nM, respectively, compared to Erlotinib (IC50 = 80 nM); they exhibited IC50 values of 76, 12, and 28 nM, respectively, compared to Olaparib (IC50 = 12 nM). They showed potent cytotoxicity against MDA-MB-231 cells with IC50 values of 16.3 ± 0.4, 1.27 ± 0.1, and 3.46 ± 0.1 μM, respectively. However, when tested against normal MCF-10 A cells, they showed low cytotoxicity and greater IC50 values. The cell cycle was halted at the G2-phase by compound 10, which promoted apoptosis 7.16-fold. The MDA-MB-231 cancer cells' apoptosis-related genes were impacted. Molecular docking analysis revealed good binding disposition of compound 10 to the two EGFR/PARP-1 target proteins.

Benzo(a)pyrene (BaP) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), as typical environmental carcinogens, are widely present in tobacco smoke and air pollution. Their combined exposure is an important cause of high incidence of laryngeal cancer. However, the molecular mechanism of their synergistic carcinogenesis remains unclear. To fill this gap, this study employed an integrated strategy combining network toxicology, multi-dimensional transcriptomics (bulk and single-cell), machine learning, molecular simulation, and cell function verification to systematically explore the mechanism by which BaP and NNK combined exposure induce laryngeal cancer. Through multi-dimensional data mining and machine learning algorithms, the core molecule FADS1 was identified. Functional enrichment analysis revealed that FADS1-related genes mainly participate in lipid metabolism reprogramming and tumor malignant phenotype regulation pathways. Molecular docking and 100 ns kinetic simulation confirmed that both BaP and NNK can stably bind to FADS1, with a stronger binding affinity for BaP (ΔG = -9.0 kilocalories/mole), and the binding mode is mainly based on van der Waals forces and hydrophobic interactions. Cell experiments demonstrated that combined exposure of BaP and NNK can significantly upregulate the expression of FADS1 in laryngeal cancer cells, enhance cell proliferation, migration, and invasion abilities, while silencing FADS1 can effectively reverse these malignant phenotypes. In summary, this study clarified the key role of FADS1 in mediating the synergistic promotion of laryngeal cancer by BaP/NNK, providing experimental support for understanding the carcinogenic mechanism of environmental compound pollutants, and also offering potential targets for risk assessment, early diagnosis, and precise prevention and control of air pollution and tobacco exposure-related laryngeal cancer.

Multi-parametric quantitative magnetic resonance imaging (mqMRI) holds significant clinical potential through multi-parametric tissue characterization, yet its adoption is hindered by prolonged scan time and sensitivity to non-ideal signal conditions, especially in high-resolution whole-brain protocols. To address these challenges, we propose a novel signal encoding method integrating phase-modulated three dimensional steady-state free precession with multiple overlapping-echo detachment (3D SSFP-MOLED). This method simultaneously encodes six physiological parameters (M0, T1, T2, T2*, B1+, ΔB0) into k-space by controlling overlapping echo detachment in signal acquisition. A physics-constrained synthetic data pipeline was developed to simulate MR signal evolutions with realistic field variations (ΔB0, B1+ inhomogeneities), enabling robust training of network for real-time parameter mapping. Whole-brain parametric maps (1×1×2 mm³ resolution) can be delivered within 3 minutes with only 2x parallel acquisition acceleration. Validation was performed on phantom, healthy volunteers, and clinical cases with tumors/hemorrhage. Experimental results show that our method can achieve rapid multi-parametric quantitation with high accuracy and reproducibility. By synergizing adaptive signal encoding, physics-informed synthetic training, and reproducible deep learning reconstruction, this work establishes a new paradigm for efficient and reliable mqMRI in clinical signal processing applications.

The epidermal growth factor receptor (EGFR) is a critical oncogenic driver in colorectal cancer, establishing the need for novel small-molecule inhibitors. We designed and synthesized two new triazole-grafted quinazolinones, T6 and T7, utilizing click chemistry to efficiently construct their hybrid architecture. Biological evaluations demonstrated that both compounds possess multi-panel antiproliferative activity across nine NCI cancer subtypes, with mean growth inhibition (GI%) exceeding 100% against CNS cancer (128.54% and 87.98%), melanoma (122.75% and 136.30%), and colon cancer (114.34% and 88.22%) for T6 and T7, respectively. In the five-dose screening, T6 and T7 showed notable activity against HT29 colon cancer cells, with GI₅₀ values of 0.53 μM and 0.39 μM, respectively. Both compounds exhibited markedly lower cytotoxicity against normal WI-38 fibroblasts (IC50: 156.59 μM for T6 and 191.80 μM for T7) compared to the reference kinase inhibitor dasatinib (IC50: 37.87 μM), supporting a favorable in-vitro safety profile. Both quinazolinones effectively inhibited EGFR kinase activity with IC50 values of 0.198 μM and 0.131 μM, respectively, compared to 0.046 μM for the reference inhibitor erlotinib. Mechanistic studies revealed that T6 and T7 induce G₀/G₁ cell cycle arrest and significantly trigger apoptosis in HT29 cells, with total apoptosis rates of 67.40% for T6 and 89.62% for T7, versus 30.16% in untreated controls. Both compounds also demonstrated notable anti-migratory effects, with T6 limiting wound closure to 16.85% and T7 to 33.71%, compared to 57.18% in untreated HT29 cells over 48 h. Molecular docking suggested favorable initial EGFR binding of the synthesized quinazolinones, while molecular dynamics analysis supported improved dynamic stability of T7 relative to T6. The results support T6 and T7 as viable and safe candidates for further development in colorectal cancer treatment.

Rapid assessment of chemotherapeutic response is essential for precision oncology but remains hindered by tumor heterogeneity and complex biological matrices. Here, we develop MetaRing, a programmable coffee-ring-derived plasmonic biosensor fabricated through dual regulation of nanoparticle concentration and evaporation temperature. This strategy enables deterministic nanoassembly, generating hierarchical structures with dense and stable nanogaps and conferring exceptional matrix robustness in water, PBS, protein-rich buffers, and complex cell lysates. MetaRing enables rapid, label-free surface-enhanced Raman spectroscopy (SERS) profiling of paclitaxel (PTX) response using minimal biological material. Distinct PTX-sensitivity fingerprints are consistently identified across drug-resistant breast cancer cell lines, xenograft tumors, and patient-derived biopsy tissues. Metabolomic analysis reveals that these spectral signatures originate from metabolic reprogramming involving arginine and methionine-cysteine pathways, providing mechanistic insight into chemoresistance. Integration with a lightweight one-dimensional convolutional neural network enables accurate classification of PTX sensitivity within 10 min without labeling or culture expansion, achieving >92% accuracy in clinical cohorts. Collectively, MetaRing establishes a robust and scalable plasmonic platform for rapid phenotypic drug response profiling with strong translational potential.