Journal of Enzyme Inhibition and Medicinal Chemistry最新文献

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.

PARP1 inhibitors are FDA-approved for BRCA1/2-mutated breast cancer but show limited efficacy in wild-type cancers and face resistance issues. To overcome these, we designed novel 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-based compounds integrating PARP1 inhibitor pharmacophores with the ATR inhibitor AZD6738 scaffold. Substituent modifications influenced PARP1 and ATR selectivity, yielding dual inhibitors or selective PARP1 inhibitors. Compound 38a, the lead candidate, exhibited potent dual inhibition (IC₅₀ < 20 nM) and strong antitumor effects in MDA-MB-231 (IC₅₀ < 0.048 μM) and MDA-MB-468 (IC₅₀: 0.01 μM) cell lines in vitro. Mechanistically, 38a arrested cell cycle progression, induced apoptosis, inhibited colony formation and migration, and suppressed DNA damage repair pathways, outperforming combined Niraparib and AZD6738. These findings underscore the therapeutic potential of PARP1/ATR dual inhibitors for breast cancer and support further investigation.

Palladium-catalysed reactions have emerged as indispensable tools in medicinal chemistry, enabling the precise construction of C-C and C-N bonds across a wide spectrum of drug-like molecular frameworks. This manuscript comprehensively examines advances reported over the past five years in palladium-catalysed methodologies applied to epigenetic drug discovery. The mechanistic diversity and synthetic adaptability of palladium catalysts for accessing scaffolds addressing the epigenetic targets have been highlighted. The robust drug design strategies and activity profile of the generated small molecule epigenetic inhibitors through palladium-assisted synthetic protocol are also presented in this compilation. Particular emphasis is placed on understanding the influence of ligand structure, base selection, and solvent optimisation in modulating catalyst reactivity. Collectively, this review offers a practical and forward-looking framework for the design and synthesis of next-generation epigenetic anticancer therapeutics (selective/non-selective/hybrid-inhibitors and degraders/PROTACS).

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.

Monoamine oxidase B (MAO-B) inhibitors may be an effective therapeutic approach for Parkinson's disease. This study designed and synthesised a series of N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalen-1-amine derivatives and evaluated their inhibitory activity against human MAO-B (hMAO-B). Most compounds exhibited inhibitory activity and selectivity, with compounds 29 and 34 demonstrating the strongest inhibitory potency (IC₅₀ = 0.066 ± 0.03 μM and 0.070 ± 0.002 μM, respectively) and selectivity indices (SI > 151 and 134), which were superior to the positive control rasagiline. Enzyme kinetic studies confirmed that these representative active compounds exhibited mixed reversible inhibition of hMAO-B. Molecular docking and kinetic analyses indicated that compound 29 binds stably to the hMAO-B active site. Concurrently, they exhibited low neurotoxicity and protective effects against 6-OHDA-induced damage in SH-SY5Y neuroblastoma cells. Therefore, we propose these active compounds as potential drug candidates for further investigation.

Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, are directly involved in the degradation of the extracellular matrix preceding uncontrolled cancer growth and metastasis. For these reasons, MMPs are considered key therapeutic targets in the development of cancer treatments. Acknowledged for its prophylactic effects against various diseases including cancer, physical exercise has been reported to boost the immune system, enhance endogenous defence mechanisms, manage oxidative stress, and regulate MMP. Despite its benefits, patients with compromised capacity for physical activity due to injuries and frailty are often unable to take advantage of them. As a possible solution for this problem, the alternative therapeutic approach of exercise mimetics has been gaining traction through pharmacological interventions. Exercise mimetics are pharmacological agents that partially mimic the molecular and physiological benefits of physical exercise without requiring actual physical activity. Recent studies have indicated that the potential of these compounds may serve as candidates for further investigation in cancer treatment. In this study, the possible anti-cancer and anti-metastatic-related effects of six selected exercise mimetics (i.e., AICAR, Icariin, Berberine, Betaine, GW501516, and Metformin) were investigated by targeting activity and/or expression of MMP-2/9 in in vitro model. These compounds (i) inhibited MMP-2 activity by interacting with the active site and/or allosteric sites, (ii) downregulated MMP-2/9 expression by influencing STAT3 signalling pathways, and (iii) reduced lung cancer cells (A549) viability to varying degrees. Among the exercise mimetics, Icariin and Berberine have relatively stronger effects on both the activity of MMP-2 and the expression of MMP-2/9 in cancer cells. These findings highlight the novel potential of exercise mimetics as targeted cancer therapeutics through the regulation of MMP activity and expression in cancer progression and metastasis.

The PCSK9-LDLR interaction, driving elevated LDL-C, is a key driver of ASCVD pathogenesis. Identifying peptides disrupting this interaction offers an alternative ASCVD therapy. Herein, via structure-based virtual screening with Pep2-8 as a control, we identified TPP-4, a high-affinity peptide inhibitor targeting PCSK9. Compared to Pep2-8, TPP-4 showed lower binding free energy (approximately -9.8 kcal/mol) and K_d values (K_d = 0.08 ± 0.01 μM), interacting with PCSK9's LDLR-binding domain through multiple interactions. CD spectroscopy also provided indirect evidence for these key interactions. Additionally, it stably bound to the LDLR binding domain of PCSK9 during 100 ns MD simulations. It showed good serum stability, negligible HepG2 cytotoxicity, and restored surface LDLR (EC₅₀ = 1.12 ± 0.05 μM). In mice, TPP-4 upregulated hepatic LDLR and reduced plasma total cholesterol levels. In conclusion, these data demonstrate that TPP-4 could be a high-affinity and potent candidate peptide for ASCVD treatment.

Nrf2 is recognised as an attractive therapeutic target for oxidative stress-related disorders through its regulation of antioxidant gene transcription. Direct inhibition of Keap1-Nrf2 protein-protein interaction represents a promising strategy to modulate Nrf2 activity. Herein, we report the discovery of meta-substituted bis(arylsulfonamido)benzene derivatives using a molecular hybridisation strategy based onpotent inhibitors 2a and 3a. Among the initial hybrids, 7a demonstrated good potency in the FP assay, making it a suitable lead for SAR optimisation. Our study found 13b was the most potent analog, showing IC₅₀ values of 183.4 nM in the FP assay and 107.5 nM in the TR-FRET assay. It also demonstrated excellent metabolic stability, with 93.9% remaining after a 30 minute-incubation in human liver microsomes. Collectively, these results highlight 13b as a non-covalent Keap1-Nrf2PPI inhibitor, with balanced potency and metabolic stability, supporting its potential as a tractable scaffold for further optimisation to modulate the Nrf2 pathway.

Thymol, an isomer of carvacrol, exhibits anti-Aβ activity. Thymol carbamates were designed, and their inhibition on cholinesterase (ChE) activity was assessed and analysed, among them, TC-4, TC-6, H4 and H5 bearing cyclic amines exhibited nanomolar inhibitory activity with IC₅₀ values of 13, 3.6, 47, and 12 nM. TC-6 bearing a piperidinyl moiety demonstrated nanomolar hBuChE inhibition (IC₅₀ = 3.6 nM), >2,500-fold selectivity over hAChE, and pseudo-irreversible kinetics (K_d = 0.25 μM, k₂ = 0.98 min^-1). TC-6 exhibited low cytotoxicity, crossed the blood-brain barrier, and protected neurons against H₂O₂-induced damage. In Aβ_1-42-induced AD mice, TC-6 (10 mg/kg) greatly enhanced cognitive abilities in MWM tests, reduced brain Aβ levels, and restored hippocampal neuron density. These results highlight TC-6 as a potent, brain-penetrant BuChE inhibitor with therapeutic potential for AD.

KRAS-G12D mutations are common drivers of pancreatic and colorectal cancers, yet effective targeted therapies remain limited. This study describes the design, synthesis, and biological evaluation of two novel KRAS-G12D inhibitors, GD-2 and GD-4. Both compounds exhibited strong antiproliferative activity in AGS and ASPC1 cancer cell lines, with IC₅。 values ranging from 0.2 to 1.8 µM. The protein binding assay also demonstrated high affinity for KRAS-G12D, with dissociation constants (Kd) of 146 nM for GD-2 and 3.18 nM for GD-4. Mechanistic investigations revealed that both compounds significantly reduced downstream, as evidenced by a clear decrease in phospho-ERK expression. Additionally, molecular dynamics simulations confirmed stable binding interactions within the KRAS-G12D pocket. Collectively, these findings identify GD-2 and GD-4 as promising therapeutic candidates for KRAS-G12D-driven cancers.