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.

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.

To address the imbalance between antibacterial potency and developability in cephalosporin discovery against Escherichia coli, we developed a comprehensive screening strategy guided by the principle of maximum drug-likeness. An integrated evaluation framework was established, consisting of 33 independent predictive submodels across five dimensions: physicochemical properties, pharmacokinetics, safety, efficacy, and stability. This framework was combined with a five-fold property-spectrum scoring mechanism (S_5F) to enable multidimensional and quantitative prioritisation of candidates based on overall developability. Application of this strategy to the eMolecules library yielded 15 high-potential candidates. Experimental results showed compound M3 as the lead molecule, exhibiting notable antibacterial activity against E. coli (minimum inhibitory concentration [MIC] = 16 μg/mL). Molecular analyses further demonstrated that M3 achieved superior binding stability relative to the reference drug Cefaclor through a multimodal, high-affinity interaction network with the target protein. This strategy reduces late-stage attrition risk and provides a robust paradigm for rational antibacterial drug discovery.

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.

Alzheimer's disease (AD) still lacks therapies that definitively halt its progression. Dual AChE/MAO-B inhibitors offer a promising strategy to address both symptoms and pathology. Here, we designed and synthesised a series of donepezil-safinamide hybrids. The optimised compound 28c was identified as a potent inhibitor of AChE (IC₅₀ = 1.70 μM) and MAO-B (IC₅₀ = 0.18 μM). Mechanistic studies indicated that 28c acts as a reversible mixed-type inhibitor of AChE and a competitive reversible inhibitor of MAO-B. Molecular docking and molecular dynamic simulations revealed that 28c could strongly and stably bind to MAO-B and AChE mainly through van der Waals interactions. Moreover, compound 28c demonstrated effective blood-brain barrier penetration, exhibited suitable stability in mouse plasma and brain homogenate, and showed a favourable safety profile both in vitro and in vivo. Furthermore, 28c could attenuate AD-related symptoms and exert hippocampal neuroprotection effect in vivo, highlighting its promise as an anti-AD candidate.

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.

To develop eco-friendly pesticides with novel modes of action for insect management, a series of dual-chiral N-cyano sulfilimine-substituted anthranilic diamides were designed and synthesised de novo, and their insecticidal activities were evaluated against Mythimna separata (M. separata) and Plutella xylostella (P. xylostella). Most target compounds exhibited potent insecticidal activity against M. separata. Notably, compounds 6a-b and 6f-g demonstrated near-complete inhibition at 0.1 mg/L, achieving efficacy comparable to the commercial standard chlorantraniliprole (CHL). Furthermore, 6g and 7h outperformed CHL against P. xylostella, suggesting enhanced specificity. 6g matchedCHL's efficacy against M. separata. Specific target compounds, including 6g and 7h, emerged as potential modulators of insect ryanodine receptor (RyR). Molecular docking revealed that 6g probably formed three hydrogen bonds with RyR binding pocket and exhibited stronger binding affinity than CHL (two hydrogen bonds). These findings provide a structural foundation for rational design of novel chiral sulfiliminyl RyR-targeting insecticides.

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.

FMS-like tyrosine kinase 3 (FLT3/CD135) regulates haematopoiesis and is frequently mutated as FLT3-internal tandem duplication (FLT3-ITD) in acute myeloid leukaemia (AML), associated with poor prognosis. Although FLT3 inhibitors show clinical benefits, resistance remains a challenge. This study hypothesises that antibody-drug conjugate (ADC) efficacy depends on distinct FLT3 trafficking mechanisms in FLT3-wt and FLT3-ITD cells. Confocal imaging showed that in THP-1 (FLT3-wt) cells, FLT3 mAb trafficked to lysosomes, while in MV4-11 (FLT3-ITD) cells, it accumulated in the Golgi. To evaluate the impact of this trafficking difference, we synthesised an anti-FLT3 mAb-MMAE, linked via a Val-Cit-PAB linker at the Fc N-glycan, which exhibited lower cytotoxicity in MV4-11 than THP-1 cells, indicating that the impaired lysosomal trafficking of FLT3-ITD limits drug release and reduces ADC potency. These findings highlight that effective lysosomal targeting is essential for ADC activity and suggest that optimising linker design or restoring lysosome trafficking may enhance FLT3-targeted ADC in AML.

Given the multifactorial aetiology of Alzheimer's disease, multi-target strategies have emerged as a promising therapeutic approach. In this study, we designed and synthesised a series of ferulic acid carbamate derivatives to selectively inhibit BuChE and stimulate Nrf2 pathway. The biological evaluation revealed that compound 5c and 5e were the most potent, exhibiting over 150-fold selectivity for BuChE. Also, 5c, 5g and 5h significantly reversed both H₂O₂^- and Aβ-induced toxicity in HT22 cells. These compounds were further shown to eliminate ROS accumulation induced by Aβ and upregulated HO-1 and GCLM by promoting the nuclei translocation of Nrf2. In Aβ transgenic C. elegans, three lead compounds alleviated Aβ-induced paralysis and cognitive deficits. In silico study revealed that compound 5c fitted well into the active sites of BuChE and Keap1 while maintaining favourable CNS drugability. This dual strategy of cholinesterase inhibition and oxidative stress mitigation is a promising approach for novel AD therapeutics.