Journal of Enzyme Inhibition and Medicinal Chemistry最新文献

UBE2C (also known as UbcH10) is a ubiquitin-conjugating enzyme essential for mitotic progression and a potential therapeutic target in cancer. Here, we report a structure-based design and characterisation of peptides derived from a natural interacting partner (U1) aimed at modulating UBE2C activity. Biophysical and biochemical assays identified peptide 5 as a lead compound, capable of binding UBE2C with micromolar affinity and inhibiting the formation of the UBE2C-Ub thioester complex. Enhanced sampling molecular dynamics simulations revealed that peptide folding landscapes are correlated with activity, with active peptides sampling transient β-sheet conformations compatible with binding. To the best of our knowledge, this is the first report of a peptide inhibitor of UBE2C enzymatic activity.

The N-acetylglucosamine-1-phosphate transferase (WecA)is a potential target for developing anti-tuberculosis drugs, due to its critical role in the synthesis of mycobacterial cell wall. The enzymatic study of WecA and the discovery of WecA inhibitors are therefore justified. However, WecA is a membrane protein with 11 transmembrane domains, making it difficult to be obtained, and even more difficult to perform activity studies. In order to gain sufficient WecA protein for activity investigation, the Escherichia coli (E. coli) Lemo21(DE3) strain was utilised in this study. The expression level of WecA was precisely regulated by T7 lysozyme. Purified WecA was obtained by affinity chromatography and identified by mass spectrometry. The kinetic properties of WecA were determined based on the detection of the product UMP. In addition, tunicamycin proved to be a competitive inhibitor. These results will lay theoretical foundations for the elucidation of WecA catalytic mechanism and the development of WecA inhibitors.

Cynanchum wilfordii is a widely used herb in Oriental medicine, known for its wide range of therapeutic applications. The present study was conducted with the aim of evaluating the effects of selected compounds isolated from C. wilfordii, including 4-hydroxyacetophenone (CW1), 2,4-dihydroxyacetophenone (CW2), wilfoside K1N (CW3), and cynandione A (CW4), on the inflammatory response induced by treatment of macrophages with LPS. The study focused on the analysis of the MAPK and NF-κB pathways. The results showed that treatment with CW1, CW2, CW3 and CW4 inhibited the expression of p-ERK, p-JNK, p-p38 and p-IkBa in LPS-induced macrophages, with CW4 exhibiting the greatest inhibitory effects. Furthermore, CW4 treatment showed the most significant inhibitory effect on p-IκB-α/IκB-α expression in the NF-κB pathway. In conclusion, the data demonstrate that CW4 exerts a robust inhibitory effect on macrophage inflammatory signalling pathways in the LPS-induced inflammatory response.

Indole is a privileged heteroaromatic scaffold in medicinal chemistry, characterised by its unique physicochemical properties, hydrogen-bonding potential, and bioisosteric versatility. Over the past decades, numerous indole-containing drugs have been approved by the Food and Drug Administration (FDA), spanning diverse therapeutic areas including oncology, infectious diseases, gastrointestinal disorders, neurological conditions, and cardiovascular diseases. This review provides a comprehensive survey of FDA-approved indole-based drugs, with particular emphasis on those approved from 2013 to the present. Representative synthetic strategies are highlighted to illustrate the versatility of the indole framework in drug design. Furthermore, we systematically discuss each drug's pharmacology, mechanisms of action, and clinical applications. By integrating synthetic chemistry with clinical applications, this review aims to provide medicinal chemists and drug developers with guidance for leveraging indole scaffolds in next-generation therapeutic discovery and development.

Docetaxel (DTX) resistance is the main cause of treatment failure in castration-resistant prostate cancer (CRPC). Pyrroline-5-carboxylic acid reductase 1 (PYCR1) is an enzyme involved in proline metabolism. It is highly expressed in various cancers and promotes malignant progression, yet its role in DTX resistance in prostate cancer remains unclear. In this study, bioinformatics analyses and in vitro/vivo experiments demonstrated that interfering with PYCR1 expression modulates the sensitivity of prostate cancer cells to DTX. Subsequently, via structure-based virtual screening, molecular dynamics simulations, and cellular thermal shift assay (CETSA), emodin-an anthraquinone compound-was identified as a PYCR1-targeting agent. Collectively, these findings suggest that PYCR1 may serve as a key target mediating DTX resistance in prostate cancer, and the emodin-DTX combination provides a promising potential clinical strategy to overcome such resistance. Finally, its functions and safety were also verified through in vitro experiments.

Lung cancer, a globally prevalent fatal malignancy, remains a major therapeutic challenge. X-linked inhibitor of apoptosis protein (XIAP) is overexpressed in various cancers, driving uncontrolled proliferation, while its specific inhibition suppresses tumour growth. Through virtual screening, we identified five novel candidate peptides (Peptides 1-5) with picomolar-level inhibitory activity. Peptide-5 showed the highest binding affinity (K_d = 10.2 ± 0.5 pM), and FP assay indicated that Peptide-5 competitively binds the BIR3 domain of XIAP against caspase-9. Molecular dynamics simulations confirmed the structural stability of its complex with XIAP. Meanwhile, Peptide-5 showed good serum and metabolic stability, as well as favourable cellular permeability. Notably, Peptide-5 exhibited potent antiproliferative activity against various tumour cells with no obvious toxicity to normal cells. Peptide-5 potentially activates apoptotic signalling through modulating the Bcl-2/Bax mRNA expression. In summary, our study confirms that Peptide-5 is a highly potent and promising XIAP-targeted inhibitor for the treatment of cancer.

TGF-β promotes progression and metastasis in later stages of tumour development, and inhibitors targeting TGF-β or its receptor have faced clinical limitations due to toxicity and poor selectivity. This study aimed to identify novel TGFβR1 inhibitors by screening the ChemDiv database using a structure-based virtual screening approach. Among the top-ranked compounds, 3282-0487 showed the highest potency. Its analogues were further evaluated, leading to four potent TGFβR1 inhibitors with sub-micromolar IC₅₀ values. Molecular docking confirmed favourable binding interactions, and structure-activity relationship analysis highlighted key structural features contributing to inhibitory activity. Among these, compound 3282-0486 demonstrated the lowest IC₅₀ values against colorectal cancer cells, inducing apoptosis and dose-dependent anti-migration effects. Its efficacy was further supported by changes in downstream TGFβR1 signalling, including p-Smad2, EMT markers, and PARP1 cleavage. Additionally, compound 3282-0486 exhibited selectivity for TGFβR1. Overall, these findings support compound 3282-0486 as a promising TGFβR1 inhibitor with therapeutic potential.

Cytochrome P4501B1 (CYP1B1), overexpressed in solid tumours but minimally in healthy tissues, is a promising anticancer target linked to chemoresistance. While CYP1B1 inhibitors can restore drug efficacy, most suffer from limited scaffold diversity and poor selectivity against other CYPs. We identified 2-(2-phenylethyl) chromones as a novel scaffold for anti-CYP1B1 activity and synthesised 24 derivatives with varied ring A/B substituents and established the SAR. Three compounds (CX-6, CX-9, CX-22) showed nanomolar anti-CYP1B1 activity and exceptional selectivity (SI > 230). In CYP1B1-overexpressing cells, the water-soluble and non-cytotoxic CX-9 (solubility > 100 μM) dose-dependently reversed docetaxel resistance, achieving efficacy at 50 μM comparable to 20 μM of the CYP1B1 inhibitor α-naphthoflavone (ANF). Molecular docking revealed similar binding modes for CX-9 and ANF in CYP1B1's active site. This work hints 2-(2-phenylethyl) chromones as a natural-derived scaffold for promising CYP1B1 inhibitor development.

Imidazole scaffolds are attractive in drug design for bioactivity and synthetic accessibility. We developed S-substituted imidazole-2-thione derivatives, focusing on compound 24, which showed potent cytotoxicity against lung, cervical, and colorectal cancer cells with submicromolar IC₅₀ and selectivity over fibroblasts. Mechanistic analyses revealed G1 arrest, caspase-dependent apoptosis, and p-γH2AX accumulation. Importantly, compound 24 strongly inhibited A-549 cell migration and invasion in both 2D and 3D assays, correlating with downregulation of MMP-2, MMP-9, and hTERT. In vitro enzyme assays further confirmed that compound 24 directly inhibits MMP-9 activity. In vivo, 24 suppressed tumour growth and vasculotropic spread in the CAM model without detectable toxicity. Docking and dynamics simulations confirmed stable binding to MMP-2 and MMP-9 active sites. These results identify compound 24 as a promising anticancer agent with both cytotoxic and anti-metastatic properties, supporting its further preclinical investigation.

The SARS-CoV-2 Main Protease (M^pro), a key enzyme for viral replication, represents a highly attractive target for the development of broad-spectrum anti-coronavirus therapeutics. The organoselenium drug Ebselen has shown potent in vitro inhibition of M^pro as well as antiviral activity, granting clinical interest as a COVID-19 treatment option. Here we show that Ebselen and selected derivatives with human neutrophil elastase (HNE) inhibition and anti-radical activity are able to bind covalently to the viral enzyme with multiple stoichiometry, exhibiting inhibitory activity towards SARS-CoV-2 M^pro with potencies in the nanomolar range. Employing a mass spectrometry-based approach, we show that, upon binding to the target, Ebselen and its derivatives induce a dose-dependent shift in the dimer-monomer equilibrium, favouring the inactive monomeric state of the viral protease and possibly contributing to the observed in vitro inhibition.