Journal of Enzyme Inhibition and Medicinal Chemistry最新文献

Poly(ADP-ribose) polymerase (PARP) inhibitors constitute a significant class of targeted anticancer therapies that leverage the principle of synthetic lethality in tumours deficient in homologous recombination (HR) repair. Although these agents have shown clinical efficacy in treating HR-deficient tumours, their wider application has been limited by challenges including the emergence of drug resistance, dependency on HR deficiency phenotypes, and related hematological toxicity. To mitigate these limitations, dual-target PARP inhibitors have emerged as a promising therapeutic strategy, simultaneously modulating PARP and synergistic pathways within a single molecular entity. This approach effectively circumvents the pharmacokinetic complexities and cumulative toxicity associated with multi-drug regimens, while simultaneously enhancing therapeutic efficacy through complementary mechanisms. This review highlights recent progress in PARP-based dual inhibitors, focusing on target selection, structure-activity relationships, synergistic antitumor mechanisms, and future research directions. It combines preclinical and clinical insights to guide the development of next-generation PARP dual-target inhibitors with improved efficacy and safety.

HIF2α is aberrantly upregulated in some renal cell carcinomas due to VHL mutations, supporting HIF2α inhibition as a compelling therapeutic approach for such cases. Therefore, the six compounds (designated as Compounds 1-6) were screened from the Maybridge database based on the constructed pharmacophore model and molecular docking. Subsequently, the docking models of Compounds 1-6 with HIF2α were analysed. Affinity assays revealed that both Compound-4 and Compound-5 exhibited robust affinity towards human recombinant HIF2α. MD simulations displayed that Compound-4 and Compound-5 stably bound to the active pocket of HIF2α. Cell experiments demonstrated that Compound-4 effectively inhibited the growth of the 786-O human renal cell carcinomas line (IC₅₀ = 1.35 ± 0.06 μM). This study demonstrates that Compound-4 may serve as a potential candidate compound for renal cell carcinomas therapy.

The liver is essential for metabolism and detoxification and can regenerate effectively. However, severe injuries or major surgeries can hinder this ability, leading to liver insufficiency or failure. Recent research has identified mitogen-activated protein kinase kinase 4 (MKK4) as a key negative regulator of liver regeneration, making it a promising therapeutic target. Inhibiting MKK4 reduces apoptosis and enhances liver regeneration, spurring interest in small molecule inhibitors of MKK4 for therapeutic strategies to promote liver recovery. This review systematically elucidates the structural characteristics and biological functions of MKK4, alongside its regulatory mechanisms in liver regeneration. It emphasises recent advancements in the research of small molecule inhibitors targeting MKK4 and offers a thorough and comprehensive analysis of the structure-activity relationships of the reported MKK4 inhibitors. The objective is to provide theoretical insights and research directions for the development of efficient and specific MKK4 inhibitors.

Due to their various pharmacological effects, several substituted sulphur heterocycles containing thiophene have recently attracted a great deal of attention. A novel 2,3-diaryl-2,3,5,6,7,8-hexahydro-4H-benzo[4,5]thieno[3,2-e][1,3]oxazin-4-one (9-14) was synthesised starting from cyclohexa[b]thiophene. Compounds 9 and 10 showed the greatest gene expression downregulation of BAX by 75.1% and 79.7%, and upregulation of Bcl-2 gene expression by 8.1 folds for each. It also decreased the level of AChE by 70.2 and 75%; respectively. Compounds 9 and 10 significantly increased Wnt3a levels by 5.8 and 6.6 folds, and β-Catenin levels by 10.1 and 10.5 folds, respectively, compared to donepezil. They significantly downregulated 5-GSK3β gene expression by 77.1%, and 78.7%, respectively. Even though all compounds exhibited potent inhibition of AChE, all synthesised compounds, except for compounds 5 and 11 demonstrated higher selectivity towards BChE (SI < 1). In-silico ADMET calculations as well as molecular docking have been performed for synthetic compounds.

Maltase-glucoamylase (MGAM) is a small-intestinal enzyme comprising two tandem α-glucosidase units, NtMGAM and CtMGAM, each capable of hydrolysing maltodextrins into glucose. MGAM serves as a therapeutic target for managing postprandial hyperglycaemia; comprehensive insights into its full-length three-dimensional structure and inhibitor kinetics remains limited. Here, we demonstrate that the α-glucosidase in porcine serum is comparable to that encoded by the MGAM gene. Using cryo-electron microscopy, we determined the complex structure of serum MGAM with the inhibitor acarviosyl-maltotriose (AC5), which was found to bind exclusively to the active sites of each unit, confirming the presence of independent catalytic sites. AC5 was shown to exhibit mixed-type inhibition towards full-length serum MGAM and competitive inhibition against both recombinant NtMGAM and CtMGAM. The apparent mixed-type inhibition can be more accurately attributed to dual competitive inhibition mechanisms. These findings contribute to the advancement of functional foods and therapeutic interventions for postprandial hyperglycaemia and type 2 diabetes.

The serine/threonine kinase IKKε is overexpressed or activated in various cancers, making it a promising therapeutic target. Through a large-scale virtual screening of over 12 million compounds, we identified N8 as a novel IKKε inhibitor, selected for its favourable docking score and drug-likeness profile. The inhibitory activity of N8 on IKKε was validated in vitro across several cancer cell lines, including HCT116 (colorectal), HepG2 (liver), T24 (bladder), MDA-MB-231 (breast), A549 (lung), and HeLa (cervical). N8 demonstrated significant reductions in cell viability, colony formation, and migration, particularly in HCT116 colorectal cancer cells, where it exhibited superior efficacy compared to established IKKε inhibitors. Mechanistically, N8's anticancer activity appears to be mediated through modulation of autophagy rather than apoptosis.

Lysine-specific demethylase 1 (LSD1) is abnormally overexpressed in various tumour tissues of patients and has been an attractive anticancer target. In this work, a potent LSD1 inhibitor (compound 14) was designed and synthesised by the molecular hybridisation strategy. It displays the potent antiproliferative activity against HepG2, HEP3B, HUH6, and HUH7 cells with IC₅₀ values of 0.93, 2.09, 1.43, and 4.37 μM, respectively. Furthermore, compound 14 is a selective and reversible LSD1 inhibitor with an IC₅₀ value of 0.18 μM and increases the methylation levels of H3K4me1/2. Molecular docking studies showed that it formed hydrogen bonds, hydrophilic interactions and hydrophobic interactions with residues of LSD1. Anticancer mechanisms demonstrated that it suppresses migration and epithelial-mesenchymal transition process in HepG2 cells. Importantly, it exhibits potent anti-liver cancer effects in vivo without obvious toxic effects. These interesting findings suggested that compound 14, a novel LSD1 inhibitor, may be a promising therapeutic agent to treat liver cancer.

Peptidomimetic inhibitors mimic natural peptide substrates, employing electrophilic warheads to covalently interact with the catalytic Cys145 of M^pro. Examples include aldehydes, α-ketoamides, and aza-peptides, with discussions on their mechanisms of action, potency, and structural insights. Non-peptidomimetic inhibitors utilise diverse scaffolds and mechanisms, achieving covalent modification of M^pro.

Decreased proteasome activity is a hallmark of brain and retinal neurodegenerative diseases (Alzheimer's, Parkinson's diseases, glaucoma) boosting the search for molecules acting as proteasome activators. Based on the hypothesis of an electrostatic key code driving catalytic core particle (20S) activation by regulatory particles (RPs), we identified the tetra-anionic meso-Tetrakis(4-sulphonatophenyl)-porphyrin (H2TPPS) as a new activator of human proteasome. By means of an integrated approach, including bioinformatics, enzymatic kinetic analysis, atomic force microscopy, and dynamic docking simulations, we show how binding of H2TPPS affects the closed/open conformational equilibrium of human 20S to ultimately promote substrate gate opening and proteolytic activity. These outcomes support our hypothesis and pave the way to the rational discovery of new proteasome allosteric modulators able to reproduce the key structural elements of regulatory particles responsible for catalytic activation.

A novel chrysin-ferrocene Schiff base (CFSB) was synthesised as a potential anticancer agent. CFSB demonstrated high cytotoxicity against cancer cells with HepG2 (liver) being the most susceptible (IC₅₀ = 3.11 µM). The compound was less toxic towards normal MRC5 cells and exhibited ∼5-fold selectivity towards most cancer cells. CFSB caused G1-phase arrest, induced caspase-dependent apoptosis by increasing Bax/Bcl2 ratio and reduced metastasis by decreasing MMP9 in HepG2. Furthermore, CFSB was inactive against CDK2, EGFR, TrkA and VEGFR, but it strongly inhibited topoisomerase II (IC₅₀ = 20 µM) with potency comparable to etoposide (IC₅₀ = 15 µM), while weak inhibition was observed against tubulin (IC₅₀ = 76 µM). DFT calculations revealed that CFSB had desirable reactivity, while docking indicated high binding affinity with topoisomerase II. Molecular dynamics and MM-GBSA analyses showed that CFSB-topoisomerase II complex was stable with favourable binding energies, while in silico ADMET studies showed drug-like properties for CFSB.