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Phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) are overexpressed in breast cancer and drive oncogenesis, rendering PI3K/mTOR inhibitors as promising therapeutic agents. However, tumor cells readily develop resistance to single-agent PI3K or mTOR inhibitors. In this study, 40 novel bis-aryl urea-linked triazine derivatives were designed and synthesized as dual PI3K/mTOR inhibitors using a scaffold hopping strategy. Their biological activities were evaluated. The results showed that J-33 was a dual inhibitor of PI3K and mTOR kinases, with IC50 values of 400.5 nM and 8.2 nM, respectively, and it inhibited other tested kinases by less than 50%. The antiproliferative IC50 value of J-33 against MCF-7 cells was 1.5 ± 0.2 μM. Hemolysis assays indicated that J-33 exhibited low hemolytic toxicity. Apoptosis and AO staining experiments demonstrated that J-33 induced apoptosis in MCF-7 cells in a concentration-dependent manner. Western blot analysis showed that J-33 significantly downregulated the phosphorylation level of the PI3K-AKT-mTOR pathway. Therefore, we conducted in vivo antitumor studies using a nude mouse model with MCF-7 cell xenografts. The results demonstrated that at the same dose of 75 mg/kg, J-33 exhibited a higher tumor inhibition rate (44.9%) compared to PKI-587 (43.6%). In summary, a highly potent and low-toxic dual PI3K/mTOR inhibitor was developed, which deserves further investigation.

Cervical cancer remains a major global health burden. Although PD-1/PD-L1 immune checkpoint blockade has expanded treatment options, durable responses are still limited. One key reason is that tumor cells sustain immunosuppression by maintaining high levels of mature, N-glycosylated PD-L1 on the plasma membrane. This limitation highlights the need for approaches that disrupt PD-L1 maturation and stability rather than merely blocking ligand-receptor binding. UM-6, a melittin-derived fusion peptide, addresses this need by retaining antitumor activity while exhibiting markedly lower hemolysis than native melittin. In tumor models, UM-6 slowed tumor progression, reduced proliferation, and increased apoptosis. In parallel, it reshaped the tumor immune microenvironment by enhancing cytotoxic T-cell activity and mitigating PD-1-associated T-cell exhaustion. Mechanistically, UM-6 impaired PD-L1 N-glycosylation and reduced PD-L1 association with STT3A, which led to endoplasmic-reticulum retention, increased polyubiquitination, and accelerated ERAD/proteasome-mediated degradation, ultimately reducing functional PD-L1 at the cell surface. Together, these results support UM-6 as a peptide-based, mechanistically distinct strategy that targets PD-L1 biogenesis to relieve immunosuppression in cervical cancer.

Histone deacetylase 6 (HDAC6) has emerged as an attractive target for its unique cytoplasmic localization and structural features among HDAC enzymes. HDAC6 inhibitors are generally composed by three main moieties, namely a cap group, a zinc binding group (ZBG) and a linker moiety connecting them. The most frequently embedded ZBGs for HDAC inhibition are represented by hydroxamic acids which, despite their strong ability in coordinating Zn2+ ions, are often related to toxicity concerns and suboptimal drug-like properties. Compelling new evidence supported the use of difluoromethyl-1,3,4-oxadiazoles (DFMOs) and trifluoromethyl-1,2,4-oxadiazoles (TFMOs) as novel ZBGs able to selectively target HDAC6 isoform. Building on our background and interest in the identification of novel spirocyclic cap groups for selective HDAC6 inhibition, we have herein investigated the effect of fine-tuning the combination of newly conceived spirofused capping moieties with traditional (hydroxamic) or heterocyclic (DFMOs and TFMOs) ZBGs. Western Blot analysis and NanoBRET assays confirmed robust HDAC6 target engagement in cell. Furthermore, mechanistic investigation was performed on DFMO- and TFMO-based compounds, confirming a time dependent tight-binding interaction within HDAC6 active site. Finally, we have engaged the best performing compounds in the evaluation of their effect in the human urothelial carcinoma cell line T24. Our findings suggest that compound 21e inhibits T24 cell proliferation by sequentially activating autophagy and apoptosis, two interconnected cell death pathways that may cooperate in mediating its anticancer effects. These results foster further optimization of our compounds and pave the way to more selective and safer HDAC6 inhibitors.

Fibroblast activation protein (FAP) over-expressed on cancer associated fibroblast represents an attractive pan-target for cancer theranostics. FAP inhibitors (FAPIs) have achieved remarkable success in cancer imaging, but its rapid blood clearance and short tumor retention limited application in radionuclide therapy. Strategies to prolong FAPI derivatives circulation, such as dimerization and albumin binding conjugates, often make limited improvement and increase background uptake. Porphyrins, are widely used as photosensitizers in photodynamic therapy, possess favorable pharmacokinetic properties including prolonged circulation and target to some tumors. Here, for the first time, we proposed integrating respective merits of porphyrin and FAPI to develop new radionuclide deliver system with ideal tumor targeting and retention for high-performance cancer endoradiotherapy. Two lutetium-177 (177Lu) radiolabeled FAPI derivatives, [177Lu]Lu-DOTA-P1-FAPI and [177Lu]Lu-DOTA-P2-FAPI were well developed and characterized, of which the anticancer effects were systematically evaluated. Both radiolabeled FAPI ligands showed excellent stability in vitro and higher specific binding ability toward FAP-positive cancer cells over widely-used 177Lu-DOTA-FAPI-04. Ex vivo biodistribution revealed much higher tumor retention ability of [177Lu]Lu-DOTA-P1-FAPI (111.26 ± 40.65 %ID/g) and [177Lu]Lu-DOTA-P2-FAPI (190.31 ± 91.16 %ID/g) compared to [177Lu]Lu-DOTA-FAPI-04 (3.69 ± 0.19 %ID/g) at 48 h. More importantly, [177Lu]Lu-DOTA-P1-FAPI and [177Lu]Lu-DOTA-P2-FAPI produced much stronger tumor growth inhibition and longer median survival in murine xenograft models than [177Lu]Lu-DOTA-FAPI-04 with equal dosage. The outcome of this work demonstrated that porphyrin modification allows a new development path and research perspective for FAPI radiopharmaceutical clinical translation.

Mitochondria are critical for the malignant proliferation of tumor cells and their adaptation to harsh microenvironments. Using baicalein as the substrate, we designed and synthesized a series of novel mitochondrial-targeting baicalein phosphonium salt derivatives, and evaluated their in vitro antiproliferative activities against four tumor cell lines (A549, HCT116, SW620, CT26) and the normal HEK293 cell line. Compound 2c exhibited potent activity against the colon cancer cell line HCT116 with an IC₅₀ of 5.17 ± 0.48 μM and a selectivity index (SI) of ≈3.42, outperforming the positive control doxorubicin (DOX, SI ≈ 2.19). HPLC analysis confirmed the accumulation of 2c in tumor mitochondria, while in silico studies suggested its binding to MTHFD2, a mitochondrially localized protein upregulated in cancer cells. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) verified that 2c directly binds to MTHFD2 intracellularly, and enzymatic assays demonstrated an IC₅₀ of 0.066 ± 0.014 μM against MTHFD2. Furthermore, 2c remarkably increased intracellular reactive oxygen species (ROS) levels, induced mitochondrial membrane potential depolarization, arrested the cell cycle at G0/G1 phase, and promoted apoptosis. In a mouse colon cancer graft model, compound 2c achieved a 49.70% tumor inhibition rate at a dose of 20 mg/kg, with no obvious abnormalities observed in major organs. In conclusion, 2c is an effective mitochondrial MTHFD2 inhibitor with potential to develop into a potent anti-colon cancer drug.

Gastric and colorectal cancers are common and deadly across the globe. Preclinical findings propose that the pairing of MET inhibitors with anti-inflammatory drugs could synergistically impede tumor growth and reshape the tumor microenvironment. This study introduces AspMet, a novel dual-targeting inhibitor of c-Met and COX-2. In vitro experiments demonstrated that AspMet significantly inhibited the proliferation of MKN45 (IC50 = 1.05 ± 0.02 nM) and SW480 (IC50 = 1.32 ± 0.01 μM) cell lines. The experimental data indicate that AspMet effectively blocks several cancer-promoting signaling pathways, including c-Met、TRKB、COX-2 and HIF-1α, significantly inhibits epithelial-mesenchymal transition, thus decreasing tumor cell migration and invasion, and causes DNA damage, resulting in G0/G1 cell cycle arrest and the initiation of apoptosis. Furthermore, AspMet has strong anti-angiogenic properties. In animal models, AspMet significantly reduced the growth of subcutaneous tumors in both gastric and colorectal cancers，and it has an extremely high bioavailability. Therefore, the dual inhibition strategy targeting c-Met and COX-2 offers a promising novel approach for the treatment of cancers, particularly inflammatory cancers.

Oral cancer and oral potentially malignant disorders (OPMDs) remain a significant challenge in diagnosis and therapy, primarily due to inherent limitations in early detection, targeted treatment, and postoperative rehabilitation. Conventional diagnostic and therapeutic modalities often lack sufficient sensitivity, specificity, and effectiveness in restoring oral function. Biomaterials including nanoparticles, hydrogels, and scaffolds, offer versatile solutions by virtue of their tuneable properties, biocompatibility, and versatility in drug delivery and tissue engineering. However, their clinical translation is limited by the need for personalisation and lingering efficacy concerns. Artificial intelligence (AI) has emerged as a transformative approach to advance the design, optimisation, and application of biomaterials in oral oncology. By integrating machine learning (ML) and data-driven modelling, AI enhances diagnostic accuracy through biosensing and radiomic analysis, guides the rational design of drug carriers and dosing regimens, and facilitates computer-aided scaffold fabrication for maxillofacial reconstruction. This review summarises recent advances at the intersection of AI and biomaterials in the context of oral cancer and OPMDs, highlighting innovations in early detection, targeted therapy, and postoperative repair. It also discusses current barriers, including data quality, model generalizability, and regulatory oversight, and outlines future directions for interdisciplinary research. When properly integrated, AI-enabled biomaterials hold considerable potential to deliver more precise, efficient, and patient-tailored solutions for oral cancer management.

Early identification of malignant ovarian tumors is critical for informing treatment decisions and enhancing patients' quality of life. As the third most prevalent gynecologic cancer globally, ovarian cancer remains challenging to diagnose due to the high cost, limited accessibility, and radiation exposure associated with current screening techniques. This study integrates surface-enhanced Raman spectroscopy (SERS) with feature selection techniques and deep learning frameworks to construct a diagnostic model for detecting ovarian cancer based on serum component analysis. The goal is to realize efficient and precise non-invasive screening for the disease. High-quality SERS spectra were first collected from serum samples of patients with clinically confirmed ovarian cancer, healthy individuals, and those with ovarian endometrioma. Subsequently, the Light Gradient Boosting Machine (LightGBM) algorithm was employed as the base classifier to perform two-stage feature selection, utilizing both the model's intrinsic feature importance scores and SHapley Additive exPlanation (SHAP) values. Finally, a Deep Neural Network (DNN) was incorporated and trained via backpropagation to optimize the weights and biases of neuronal connections, thereby improving the predictive performance of the overall network model. After feature selection, the DNN algorithm achieved an accuracy rate of 92.03% in the five-fold cross-validation for the three types of recognition - healthy individuals, ovarian cancer, and potentially malignant ovarian endometrioma. In the evaluation of the independent test set, the accuracy rate still reached as high as 86.96%. In addition, compared with traditional machine learning algorithms, the classification performance of DNN is also the best. The findings above demonstrate that the integration of serum SERS with the robust LightGBM-DNN algorithm offers a promising strategy for clinical ovarian cancer screening.

FLT3 mutations, including internal tandem duplications (ITD) and tyrosine kinase domain (TKD) variants, are key drivers of acute myeloid leukemia (AML) and represent attractive therapeutic targets. Guided by a scaffold-hopping strategy based on G-749 (denfivontinib), a series of quinazoline-based derivatives was designed and synthesized to explore structure-activity relationships (SAR). Among them, compound W4 showed the most promising profile, exhibiting potent antiproliferative activity against MV4-11 and MOLM-13 cells and strong inhibition of FLT3-ITD (IC50 = 16.0 nM) and FLT3-D835Y (IC50 = 20.4 nM), while displaying negligible activity toward c-KIT kinase (IC50 > 100 μM). Mechanism studies indicated that W4 induced G0/G1 cell cycle arrest and apoptosis, accompanied by a reduction in intracellular reactive oxygen species levels and a loss of mitochondrial membrane potential. Collectively, these results identified W4 as a potent FLT3 inhibitor and provided valuable SAR insights for further scaffold optimization.

Tropomyosin receptor kinase (TRK) plays a critical role in tumorigenesis, and its aberrant activation is strongly implicated in cancer progression and metastasis. In this study, a series of novel indoline-2-one derivatives were designed and synthesized using a 3D-QSAR-guided approach targeting TRK. The antitumor potential of these compounds was evaluated through a panel of in vitro bioassays. Several derivatives were found to reduce TRK phosphorylation levels in a cellular context and exhibited pronounced anti-proliferative and anti-migratory effects. Among them, compound IIIc demonstrated potent activity against HepG2 hepatocellular carcinoma cells, with an IC₅₀ value of 2.06 μM. Furthermore, ELISA-based phosphorylation assays revealed that treatment with compound IIIc resulted in decrease in TRK phosphorylation, yielding an IC₅₀ of 0.19 μM, highlighting its therapeutic promise. Collectively, this study provides experimental evidence and a structural basis for the development of lead compounds capable of modulating TRK signaling in cancer therapy.