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Cyclin-dependent kinase 4/6 (CDK4/6) plays a pivotal role in cell cycle regulation, and its abnormal activation is closely associated with the initiation and progression of breast cancer.1 However, the limited number of clinically available CDK4/6 inhibitors restricts treatment options. This study focuses on the design, synthesis, and antitumor activity investigation of novel CDK4/6 inhibitors.Employing computer-aided drug design (CADD) strategies and utilizing drug-like and bioisostere principles, we innovatively introduced pyridine-2-aminopyrimidine, thieno[3,2-d]pyrimidine, and pyrazolo[1,5-a]pyrimidine as core skeletal structures to design and screen 250 compound molecules. Based on computational results, including molecular docking and MM/GBSA binding free energy, 40 potential novel CDK4/6 inhibitors were selected for synthesis.Cellular assays validated that compound 3c exhibited the strongest inhibitory activity against CDK4/6 in breast cancer cell lines, with IC50 values of 0.11 ± 0.01 μM (MCF-7), 0.21 ± 0.01 μM (4T1), and 0.12 ± 0.01 μM (MDA-MB-231). And compound 3c demonstrated favorable CDK4/6 inhibition rates and showed a certain degree of selectivity among 23 kinases. In vitro mechanistic studies revealed that 3c consistently inhibited cell colony formation and migration. Furthermore, 3c effectively arrested the MCF-7 cell cycle at the G1 phase and induced apoptosis. In the MCF-7 xenograft model, compound 3c achieved a tumor inhibition rate of 45.20%, highlighting its significant potential as a therapeutic CDK4/6 inhibitor.

This study reports the rational design, synthesis, and preliminary evaluation of a novel series of quinazolin-4-one derivatives. These compounds were developed as potential dual inhibitors of EGFR and c-SRC kinases to explore their utility in addressing bypass-related signaling in cancer cells. Through systematic optimization, compound 9b emerged as a lead candidate, demonstrating potent and balanced enzymatic inhibition with IC50 values of 0.057 μM (EGFR) and 0.073 μM (c-SRC). To our knowledge, this represents an unprecedented achievement in the development of dual EGFR/c-SRC inhibitors with this potency profile. In cellular assays, 9b exhibited significant antiproliferative activity, induced G0/G1 cell cycle arrest, and triggered apoptosis via modulation of p53, Bax, and Bcl-2 expression. Molecular docking and dynamics simulations confirmed stable binding modes within both kinase active site key amino acids, forming critical hinge-region interactions. Computational ADMET predictions further support its favorable drug-like properties. Collectively, 9b represents a promising dual-targeted therapeutic lead worthy of advanced preclinical development.

Tumor-derived exosomes carry multidimensional molecular cargo, including surface proteins, microRNAs, and lipids that encode tumor identity and disease dynamics. These features support their application as biomarkers for liquid biopsy-based cancer diagnostics. Circulating tumor DNA undergoes rapid nuclease-mediated degradation, whereas exosomes retain stable molecular information that reflects the proteomic, transcriptomic, and metabolic states of parent tumor cells. However, clinical translation of exosome-based sensing remains limited by variability in isolation, biological heterogeneity, and the analytical difficulty of detecting low-abundance biomarkers in clinical samples. In this review, we examine cancer-specific exosomal signatures across breast, lung, colorectal, and gastric cancers and evaluate biosensing platforms for exosomal biomarker profiling. We integrate engineering principles, clinical performance metrics, and AI-assisted analysis across complementary biosensing modalities to establish a cross-platform analytical framework. We compare optical platforms based on surface plasmon resonance, localized surface plasmon resonance, and surface-enhanced Raman scattering with photoluminescence- and electrochemical-based platforms in terms of sensitivity, clinical compatibility, and translational potential. Furthermore, we examine artificial intelligence (AI)-assisted biosensing frameworks, including classical machine learning classifiers, deep convolutional networks, ensemble models, explainable AI methods, and large language model interfaces. We evaluate how each framework addresses high-dimensional spectral complexity, nonlinear relationships among signals, and inter-patient variability in exosomal data. Finally, we identify remaining challenges, such as the lack of standardized isolation protocols and the absence of large-scale clinical validation. We further highlight minimal residual disease monitoring and early-stage cancer detection as important and underexplored directions for AI-integrated exosomal biosensing in precision oncology.

Recent advances in T cell-based immunotherapies highlight the urgent need for precise and dynamic monitoring across the entire cell culture pipeline. In contrast to conventional morphological assessment methods remain limited by subjectivity and static analytical paradigms, rendering them insufficient for real-time, in-process monitoring in T cell manufacturing. This capability is particularly critical for emerging metabolic reprogramming strategies, where optimizing therapeutic outcomes requires real-time tracking of dynamic cellular responses that static methods cannot provide. Here, we report a fully automated, label-free monitoring platform constructed with 3D-printed modular components that integrates automated T cell culture, real-time bright-field imaging, and deep learning algorithms. This system enables continuous tracking of T cell morphology, viability, and migratory behavior, achieving a mean average precision above 96% in cell detection and phenotypic characterization. This cost-effective architecture supports data-driven optimization of T cell expansion and provides a versatile process analytical technology for cancer immunotherapy research.

Calcium ions (Ca2+) serve as a pivotal intracellular second messenger, participating in core physiological processes including cell proliferation, neurotransmission, and apoptosis. The maintenance of calcium homeostasis depends on the precise interplay of plasma membrane channels and intracellular organelle stores. Dysregulation of calcium signaling is implicated in the pathogenesis of multiple diseases, including Alzheimer's disease, cancer, and cardiovascular disorders. Conventional pharmacological interventions are limited by off-target effects, insufficient bioavailability, and a lack of temporal and spatial control. Ca2+-regulated nanoplatform achieves spatiotemporally controlled drug release and responsive calcium level modulation through advanced surface engineering and stimulus-responsive design, substantially improving therapeutic precision and efficacy. Furthermore, nanoprobes permit real-time monitoring of calcium dynamics with high sensitivity and resolution. This comprehensive review systematically summarizes and highlights significant advances in engineering versatile nanoplatforms for calcium homeostasis modulation, focusing on constructed nanocarriers for drug delivery, functional nano-regulators for calcium flux intervention, and sensitive nanoprobes for real-time calcium imaging and quantification. Current challenges and future directions are also discussed to inspire the development of next-generation nanotheranostic platforms for precise diagnosis and treatment of calcium homeostasis-related diseases.

Nur77, an orphan nuclear receptor, is involved in the development and progression of multiple tumors. In our previous study, we have shown that the protein level of Nur77 is elevated in colon tumors compared to adjacent normal tissues, highlighting its potential as a promising target for colorectal cancer therapy. Significantly, we have identified BI1071 as a Nur77-targeting compound that induces apoptosis in colorectal cancer cells. Based on the scaffold of BI1071, by substituting the indole group of BI1071 with a pyrrolyl group on one side, we rationally designed and synthesized a series of novel BI1071 analogues named SIM-C-PhCF3+Cl- targeting Nur77, and the structure-activity relationship of these BI1071 derivatives was summarized. From this series of compounds, A6 exhibited the strongest binding affinity to Nur77 (Kd = 0.40 ± 0.05 μM) and the most potent anti-proliferative activity against HCT116 and MC38 colorectal tumor cell lines, with IC50 values of 0.53 ± 0.06 μM and 0.16 ± 0.007 μM, respectively. Interestingly, unlike BI1071, which triggers Nur77-dependent apoptosis, compound A6 suppressed colon cancer cell proliferation predominantly by inducing Nur77-dependent mitotic arrest. Collectively, our findings provide a foundation for further investigation and development of Nur77-targeting antimitotic molecules toward colorectal cancer therapy.

Depletion of the splicing factor RBM39 disrupts spliceosome function and induces widespread RNA splicing defects, leading to antiproliferative effects in susceptible cancer cells. Here, we report the discovery and characterization of a new series of biphenyl-containing RBM39 degraders. The lead compound 42 promotes RBM39 degradation through formation of a ternary complex with RBM39 and DCAF15/DDB1 in a Cullin-RING E3 ligase- and proteasome-dependent manner, consistent with a molecular glue mechanism. Transcriptomic analyses in HCT-116 and K562 cells revealed extensive alternative splicing alterations and suppression of cell-cycle-associated pathways, resulting in G2/M-phase arrest without apoptosis. Comparative cellular profiling identified 41 (YSA64) as a potent analog in acute myeloid leukemia MV4-11 cells and Ewing sarcoma A673 cells, disease contexts that have been minimally explored for RBM39 degraders. Notably, 41 exhibited favorable oral pharmacokinetics and significant antitumor efficacy in MV4-11 xenograft models. Collectively, this work expands the chemical space of RBM39 degraders and supports their continued development as RNA splicing-targeted anticancer agents.

The urinary system regulates waste filtration and fluid homeostasis, yet disorders such as chronic kidney disease, urinary tract infections, prostate cancer, and urinary stones remain major global health challenges. Current diagnostic and therapies are limited by low sensitivity, poor temporal resolution, and lack of real-time physiological feedback, hindering early intervention and precision treatment. Recent advancements in sensor technology offer innovative solutions, enhancing early diagnosis, disease monitoring, and treatment precision. This review highlights physical sensors, biomarker detection sensors and imaging-assisted sensors for urinary applications. These sensors enable early screening, continuous monitoring and precise treatment of urinary diseases, enhanced surgical navigation and personalized medication. Despite rapid progress, challenges remain in long-term biocompatibility, clinical translation, and multimodal data integration. Addressing these barriers through materials innovation and AI-driven sensor fusion will be critical for next-generation intelligent urological systems, ultimately advancing precision medicine and improving patient outcomes. This review underscores the transformative impact of sensors in urology and the need for continued innovation.

The fibroblast growth factor receptors (FGFRs) have garnered considerable attention as promising therapeutic targets in oncology, given their pivotal involvement in regulating cell proliferation, differentiation, and various other physiological processes. In this study, we have designed and synthesized a series of FGFR inhibitors featuring the 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one scaffold as a core structural motif. Notably, among these derivatives, compound 1a emerged as a potent inhibitor of four distinct FGFR subtypes, demonstrating superior efficacy in suppressing the proliferation of Huh7 hepatocellular carcinoma cells compared to BGJ398, a clinically validated FGFR inhibitor. In preclinical evaluations, 1a exhibited remarkable pharmacokinetic properties (oral bioavailability = 66.9%). In Balb/c mice bearing Huh7 xenografts, 1a achieved a 90.5% tumor growth inhibition rate at a dose of 50 mg/kg, with no discernible signs of systemic toxicity. Collectively, these findings indicate that 1a holds great potential as a broad-spectrum FGFR inhibitor for cancer treatment, supporting its further development in clinical settings.

Targeting cancer stem cells (CSCs) has emerged as a promising strategy for cancer therapy and prevention. The human cytochrome P450 enzyme CYP4Z1 has been identified as a potential therapeutic target due to its role in promoting breast cancer stemness. Aiming to develop potent and selective CYP4Z1 inhibitors, our strategy involved systematic structure-activity relationship (SAR) studies of the lead compound XD-2 (1-benzyl-1H-imidazo [4,5-c] pyridine), which led to its structural optimization. A series of derivatives were designed and synthesized to enhance drug-like properties, inhibitory activity, and selectivity. Among all the synthesized compounds, the preferred analog C8, which features an imidazo[4,5-c]pyridine core connected to a terminal butyl group via an amide-containing linker, exhibited the most potent CYP4Z1 inhibitory activity, with an IC50 value of 55.3 nM against CYP4Z1. Molecular docking studies revealed that the introduced side chain extended into the hydrophobic subpocket and the phenyl group established additional aromatic stacking interactions with Trp120. Subsequent in vitro and in vivo biological assessments confirmed that compound C8 potently diminished stemness marker expression, impeded spheroid formation, and attenuated both metastatic potential and tumor-initiating capacity in breast cancer cells. Collectively, these results underscore the promise of C8 as a leading candidate for advancing clinically viable CYP4Z1-targeted therapies in breast cancer.