Quaternary benzo[c]phenanthridine alkaloids (QBAs), an important class of natural isoquinoline alkaloids, possess potential multiple anti-cancer activities. By structural simulation, 29 2-phenylphthalazin-2-iums with anti-cancer effects were designed and synthesized in our previous study. Breast cancer is one of the most frequent malignant tumors, which is closely related to the high mortality rate in women. The role and underlying mechanism of 2-phenylphthalazin-2-iums in repressing the growth and metastasis of human breast cancer were explored. The role of 2-phenylphthalazin-2-iums in regulating the proliferation and invasion of MCF-7 cells was evaluated in vitro and in a xenograft model. After treatment with 3',5'-diCl isomer (29), the reactive oxygen species (ROS) levels, Fe2+ concentration and glutathione (GSH) contents were assessed to evaluate the effect of the 2-arylphthalazine salts on facilitating ferroptosis in MCF-7 cells. Compound 29 exhibited a dose- and time-dependent cytotoxicity on MCF-7 cells. Compound 29 treatment effectively repressed the growth and metastasis of breast cancer in a xenograft model. We verified for the first time that compound 29 triggered ferroptosis of MCF-7 cells, as evidenced by increased Fe2+ concentration, ROS level, and decreased GSH content. Mechanistically, compound 29 induced oxidative damage and ferroptosis via regulating p53/SALC7A11 axis. Iron chelator deferoxamine restored the proliferation and invasion of MCF-7 cells treated with compound 29 through inhibiting ferroptosis. Significantly, compound 29 inhibited the growth of human breast cancer cells MCF-7-derived tumor xenograft (CDX) models. Thus, 2-phenylphthalazin-2-iums represent promising leads for the development of novel anti-breast cancer agents in the future.

Gout and hyperuricemia, prevalent metabolic disorders, are driven by elevated serum uric acid (UA) levels and subsequent monosodium urate crystal deposition, which provoke inflammatory responses and joint damage. Current therapeutic options remain unsatisfactory, underscoring the urgent need for novel agents with improved efficacy and safety profiles. In this study, we aimed to discover a new lead compound capable of concurrently addressing both hyperuricemia and associated inflammatory pain. Two novel compounds were designed and synthesized, among which C2 was identified as a promising candidate. In vitro, C2 exhibited potent dual inhibitory activity against transient receptor potential vanilloid 1 (TRPV1)-a key mediator of inflammatory pain signaling-and urate transporter 1 (URAT1), which regulated renal UA reabsorption, with IC₅₀ values of 78.52 ± 14.50 nM and 598.6 ± 115.5 nM, respectively. In vivo, oral administration of C2 (20 mg/kg) significantly reduced serum UA levels in a hyperuricemic mouse model, demonstrating efficacy comparable to dotinurad. Furthermore, in a formalin-induced inflammatory pain model, C2 produced dose-dependent antinociceptive effects. Mechanistic investigations revealed that C2 suppressed NLRP3 inflammasome activation in THP-1 cells, as indicated by reduced IL-1β secretion. Additionally, C2 ameliorated dextran sulfate sodium-induced colitis in mice, accompanied by improved histopathological scores. Collectively, these results establish C2 as a multi-target lead compound that acts simultaneously on UA transport, nociceptive signaling, and the NLRP3 inflammasome pathway, providing a strong rationale for its further development as a novel therapeutic strategy for gout and hyperuricemia.

Chalcones are versatile scaffolds with broad pharmacological relevance, particularly as anti-inflammatory and anti-malarial agents. In the current investigation, a series of (3-arylediene-1-phenyl-1H-pyrazol-4-yl)acryloyl-4-hydroxy-6-methyl-2H-pyran-2-one analogs/1,3-diarylprop-2-en-1-ones were successfully synthesized, leveraging dehydroacetic acid (DHA) as the precursor molecule. The choice of DHA is strategic as it is a bioactive and highly versatile scaffold bearing a 4-hydroxy-6-methyl-2H-pyran-2-one moiety, which enhances structural diversity and provides multiple reactive sites for functionalization. Its inherent anti-microbial, anti-inflammatory, and anti-malarial potential offers an added advantage over conventional precursors, thereby increasing the likelihood of generating pharmacologically active chalcone hybrids. The synthetic protocol employed in this study involved the implementation of a Claisen condensation reaction, wherein DHA was reacted with formyl pyrazole to afford the corresponding chalcones, with yields ranging from moderate to good. The synthesized compounds were subjected to a rigorous characterization protocol, involving a battery of analytical techniques, including 1H-NMR, 13C-NMR, FT-IR, and HRMS analyses. Biological evaluation focused on anti-malarial and anti-inflammatory activities, while molecular docking (PyRx 0.8) was performed to explore binding interactions with cyclooxygenase-2 (COX-2; PDB ID: 3LN1) and enoyl-acyl-carrier-protein reductase (EACPR; PDB ID: 1NHG). Notably, compound 3c emerged as the most potent one within the synthesized series, exhibiting remarkable anti-inflammatory and anti-malarial potency, as evidenced by its IC50 values of 7.05 ± 0.17 µM and 0.95 ± 0.06 µM, respectively. Docking studies revealed strong binding affinities and favorable molecular interactions, supporting the observed bioactivities. This study highlights chalcone-pyrazole hybrids as promising therapeutic scaffolds. In particular, compound 3c emerges as a compelling lead candidate for further optimization and preclinical investigation as a dual-action agent against malaria and inflammation.

Alzheimer's disease (AD) is a progressive and complicated neurodegenerative disorder that mostly affects the elderly and is characterized by memory loss, cognitive dysfunction, accumulation of amyloid beta (Aβ) plaques, neurofibrillary tangles, and cholinergic deficits. Current therapies used for AD, such as acetylcholinesterase inhibitors and NMDA receptor antagonist memantine, can only provide temporary or symptomatic relief, but they do not stop or reverse the progression of the disease. Numerous pathogenic hypotheses have been proposed to explain this mechanism; however, the amyloid cascade hypothesis remains the most widely accepted theory, as it suggests that β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) plays a critical role in the generation of Aβ peptides. Therefore, BACE1 may be a key therapeutic target. This review primarily focuses on the key role of BACE1 in AD pathogenesis and describes the development of its inhibitors over three generations, explaining their structure, design, and pharmacological properties. While the first generation lacked brain penetration, the second-generation improved potency but encountered clinical trial failures due to adverse effects. The third generation of these drugs was designed to achieve a balance between efficacy, selectivity, and safety. Additionally, we review the promising molecules currently under clinical investigation, highlighting both their therapeutic potential and the challenges that remain in developing effective disease-modifying therapies for AD treatment.

ABSTRACTProteolysis targeting chimeras (PROTACs) and molecular glues induce ligand‐mediated ternary complexes between an E3 ubiquitin ligase and a protein of interest, but their in silico modeling remains challenging due to conformational flexibility and weak protein‐protein interfaces. Recent diffusion‐based AI structure prediction models enable the direct prediction of protein‐ligand complexes. Here we benchmarked AlphaFold 3 and Boltz‐2 for predicting PROTAC‐ and molecular glue‐mediated ternary complexes using a reproducible evaluation workflow. We curated a dataset of 40 experimentally resolved complexes from the Protein Data Bank, including 25 PROTAC and 15 molecular glue systems. Structural accuracy was assessed using complex RMSD and DockQ scores relative to the corresponding crystal structures and compared to model‐internal confidence metrics. Both models outperform other current approaches in both accuracy and runtime. Boltz‐2 shows higher prediction accuracy assessed by complex RMSD and DockQ scores. Predictions are generally more accurate for VHL‐based PROTACs than for CRBN‐based PROTACs. Predictions for molecular glue complexes show good overall accuracy. Error analysis indicates that prediction failures predominantly arise from misoriented global arrangements and twisting in flexible ternary complexes, while individual protein and ligand structures are often accurately modeled. Limitations in the generalizability of the models could also be observed, especially for more recently released structures. These findings suggest that diffusion‐based AlphaFold‐type models show promise in the structure‐based prediction of PROTAC‐ and molecular glue‐mediated ternary complexes.

ABSTRACT Indicaxanthin, a prominent betalain pigment known for its bioactivity and safety, has long been valued in traditional medicine for its antioxidant and anti‐inflammatory effects. The leading cause of liver failure and dysfunction is hepatic ischemia–reperfusion (I/R) injury, which frequently happens during hemorrhagic shock, hepatectomy, and liver transplantation. Given the increasing global incidence of hepatic disorders, especially those involving ischemic damage and inflammation‐mediated apoptosis, there is a pressing need for therapeutic agents that can target key molecular pathways. Liver ischemia and injury often result in the upregulation of inflammatory cascades, notably involving NF‐κB p65, and pro‐apoptotic markers such as caspase‐3, both of which play central roles in hepatocellular injury. We constructed a protein–protein interaction (PPI) network integrating predicted indicaxanthin targets with liver ischemia‐related proteins. The network identified NF‐κB p65 and caspase‐3 as central hubs, functionally associated with pro‐inflammatory and apoptotic pathways. Gene Ontology and KEGG enrichment analyses further implicated TNF, IL‐17, and Toll‐like receptor pathways, highlighting the broader regulatory role of indicaxanthin in hepatic stress signaling. Molecular docking against NF‐κB p65 (RelA) revealed a strong binding affinity (−6.89 kcal/mol), with key hydrogen bond interactions involving Lys221, Arg246, Val244, and Gln241. Subsequent molecular dynamics (MD) simulations confirmed the structural stability of the complex, showing low RMSD drift, consistent hydrogen bonding, compact ligand behavior, and favorable energy profiles over 100 ns. Furthermore, hepatic IRI was induced in male Wistar rats, and then the hepatoprotective effect of indicaxanthin was studied at histopathological, molecular, and biochemical levels.

Effective pain management in veterinary medicine often utilizes multi-drug formulations containing Metamizole sodium (MT), Paracetamol (PA), and Diclofenac (DI). However, severe spectral overlap makes their simultaneous quantification by spectrophotometry challenging, often requiring less green chromatographic methods. This study introduces AutoRegress, a novel Automated Machine Learning (AutoML) framework designed to overcome this limitation by automating the entire chemometric model development workflow. AutoRegress orchestrates a competitive evaluation of diverse regression algorithms and feature selection techniques, revealing that the optimal analytical model is analyte-specific-a key insight challenging the conventional 'one-size-fits-all' approach. The framework objectively identified a Lasso regression for MT, a non-linear Support Vector Regression (SVR) for PA, and a distinct Lasso model for DI. These tailored models demonstrated exceptional predictive accuracy (R2 > 0.988) on an independent test set. By providing the robust computational solution needed to deconvolve the complex spectra, AutoRegress enables the use of a rapid, green analytical method. The primary contribution is a reproducible platform that automates complex model selection, provides deeper chemometric insights, and makes advanced analytical solutions more accessible for routine quality control.

Malignant tumors have become the second leading cause of death after cardiovascular and cerebrovascular diseases, with their incidence and mortality rates remaining persistently high. Since the discovery of cisplatin's potent antitumor effects, platinum-based drugs have become a cornerstone in cancer therapy. However, the development of resistance and toxicity to normal cells following long-term use of platinum-based drugs poses significant challenges for patients. This has spurred researchers to actively explore novel platinum-based anticancer agents. Among these, platinum(IV) compounds offer a promising solution to the aforementioned issues and are gradually emerging as a viable approach in cancer treatment. This study provides an in-depth review of recent advancements in this field, emphasizing the critical need for developing strategies to control intracellular reduction of Pt(IV) prodrugs. Additionally, it explores how the axial ligands of platinum(IV) prodrugs enhance the cancer-targeting properties of platinum(IV) prodrugs and achieve synergistic effects through controlled release via external mechanisms in cancer cells, thereby reducing the toxic side effects of platinum drugs and lowering drug resistance. Furthermore, this review addresses current challenges in the field and offers insights into potential future research directions. Its analysis aims to assist researchers in rationally designing safe and efficient platinum(IV) prodrugs for precision cancer therapy.

The emergence of the EGFR C797S mutation poses a significant challenge in the treatment of non-small cell lung cancer due to resistance to third-generation EGFR-tyrosine kinase inhibitors. This study introduces a novel and highly selective EGFR PROTAC, HBE-843, designed to degrade mutant EGFR while sparing wild-type EGFR. Our degrader not only effectively degrades the L858R but also shows promising activity against exon 19 deletion, T790M, and C797S, where it demonstrated low nanomolar GI50 (26-103 nM) across all these EGFR mutant-harboring cell lines while sparing the wild-type. HBE-843 effectively reduced EGFR protein levels in mutant cells in a dose-dependent manner, with a DC50 in the low nanomolar range (1.9-18 nM) and a Dmax above 90%. Mechanistic studies showed that HBE-843 mediates EGFR degradation through the CRBN-associated proteasome pathway, preventing the activation of the ERK downstream signal and hindering cell growth. In vivo studies demonstrated a 112% tumor growth inhibition in L858R-induced cancers. These findings suggest that HBE-843 holds promise as a lead compound for developing new drugs to overcome C797S mutant-mediated resistance in clinical settings.

Hematopoietic progenitor kinase 1 (HPK1) acts as a negative regulator of T-cell receptor signaling, making it a high-priority target for cancer immunotherapy. Addressing the scarcity of structurally novel HPK1 inhibitors, we constructed and validated a comprehensive high-throughput virtual screening (HTVS) workflow to screen the ChemDiv database. This hierarchical protocol, characterized by a hybrid docking strategy and MM/GBSA rescoring, identified 10 candidates for biological testing. Experimental evaluation confirmed compound 8 as a potent hit, exhibiting an IC50 of 1585 nM and 91.65% inhibition at 25 μM. Subsequent 500 ns molecular dynamics simulations validated the stability of the compound 8-HPK1 complex (ΔGbinding = -41.59 kcal/mol), driven by critical interactions with residues GLU92 and CYS94. These findings establish compound 8 as a promising scaffold for structural optimization and demonstrate the robustness of our computational framework for HPK1 inhibitor discovery.