Journal of Enzyme Inhibition and Medicinal Chemistry最新文献

The soluble epoxide hydrolase (sEH) has recently emerged as a promising target for the treatment of several pain-related conditions. Herein, we report the design and synthesis of a peripherally restricted sEH inhibitor with high potency and good Drug Metabolism and Pharmacokinetics (DMPK) properties. Molecular dynamics and X-ray crystallography helped reveal the binding of these inhibitors to sEH. The selected compound showed a robust analgesic effect in a dose-dependent manner in a murine model of chemotherapy-induced neuropathic pain (CINP). Moreover, the compound also prevented the development of paclitaxel-induced neuropathic pain. Overall, these results suggest that peripheral inhibition of sEH might constitute a novel therapy to prevent and treat CINP.

FDA-approved kinase inhibitors represent a rapidly growing class of targeted therapies with proven clinical success in oncology. However, their occupancy-driven mode of action is often associated with resistance, off-target effects, and incomplete inhibition. Proteolysis-Targeting Chimaeras (PROTACs) offer a compelling alternative by promoting complete degradation of oncogenic kinases, thereby enhancing selectivity and resistance reduction. In this review, we provide a comprehensive overview of the rational design, development, and synthetic approaches for PROTACs incorporating FDA-approved kinase inhibitors. We discuss key aspects influencing degrader efficiency, including kinase selectivity, linker design, E3 ligase recruitment, and synthetic strategies. Additionally, we highlight recent advances, emerging trends, and future directions, such as expanding the repertoire of degradable kinases, optimising linker chemistry, and broadening diversity of E3 ligases. A better understanding of these factors will facilitate the continued evolution of PROTAC technology into effective next-generation therapies for kinase-driven diseases.

Overactivation of the epidermal growth factor receptor (EGFR) is prevalent in various tumours, rendering it a promising target for cancer therapy, particularly in the treatment of non-small cell lung cancer (NSCLC). Although the first through third generations of EGFR tyrosine kinase inhibitors (TKIs) have demonstrated significant efficacy, the emergence of drug resistance continues to pose a challenge. Current research is now focused on fourth-generation EGFR-TKIs, which specifically target the EGFR harbouring the C797S mutation. This review examines the design strategies, antitumor activity both in vivo and in vitro, binding modes, pharmacokinetics, as well as the advantages and disadvantages of each inhibitor, alongside the progress of clinical stage research related to fourth-generation inhibitors. Additionally, the review discusses future development directions for fourth-generation EGFR-TKIs, aiming to provide insights for successful research and development in this field.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase that plays a pivotal role in immune signalling and cytokine regulation, making it a compelling target for the treatment of inflammatory and autoimmune diseases. We initiated a drug discovery campaign based on the N²,N⁴-diphenylpyrimidine-2,4-diamine (DPDA) scaffold, employing an integrated strategy that combined structure-based de novo design, three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling, and biochemical evaluation. This approach emphasised the optimisation of membrane permeability by controlling the 1-octanol/water partition coefficient (LogP), while also enforcing configurational constraints to enhance IRAK4-specific binding. Through iterative cycles of computational modelling and chemical synthesis, we identified 10 out of 17 newly synthesised compounds that exhibited potent IRAK4 inhibition at low-nanomolar concentrations in both enzymatic and cellular assays. Among these, compounds 10 and 13 stood out, demonstrating strong IRAK4 inhibitory activity, favourable membrane permeability, and minimal off-target kinase interactions.

Pancreatic cancer is among the most lethal malignancies, with a five-year survival rate of only 6%. For patients with metastatic disease, current treatments extend median survival by merely four months. This study addresses the urgent need for targeted therapies, as no specific drugs are currently available. Clinical analyses revealed significantly elevated RSK2 expression in pancreatic cancer tissues, associated with shorter survival. We aimed to identify a novel RSK2 inhibitor for metastatic pancreatic cancer. Through structure-based virtual screening, we identified NSYSU-115 as a promising candidate with an IC50 of 45.5 nM. At low concentrations, NSYSU-115 significantly suppressed colony formation, while higher concentrations reduced cell viability and proliferation. It also inhibited phosphorylation of IκBα, a known RSK2 substrate, in a dose- and time-dependent manner. Furthermore, NSYSU-115 impaired cell migration and altered epithelial-mesenchymal transition (EMT) markers. These findings highlight NSYSU-115 as a potent kinase inhibitor with promising therapeutic potential for pancreatic cancer treatment.

Human aldo-keto reductase 1C3 (AKR1C3) is a steroid modifying enzyme involved in cancer progression. Here, A-ring modified 17α-picolyl and 17(E)-picolinylidene androstane derivatives are shown to inhibit AKR1C3 activity in vitro. None of the androstane derivatives have off-target affinity for the androgen receptor, based on a fluorescence assay in yeast cells. The X-ray structure of AKR1C3 in complex with the strongest inhibitor, a 17α-picolyl androstane with a C3-oxime modification, was determined at 1.7 Å resolution. Based on this crystal structure and molecular docking, inhibition of AKR1C3 by the 17α-picolyl or 17(E)-picolinylidene derivatives depends on interactions between the C3 modification and the NADP⁺ cofactor, while the C17α-picolyl or C17-picolinylidene group anchors the inhibitor to AKR1C3. Because one AKR1C3 inhibitor identified here was also previously reported to inhibit CYP17, it may be possible for future researchers to design dual AKR1C3/CYP17 inhibitors based on a steroid scaffold for potential treatment of advanced prostate cancers.

Two edaravone derivatives were synthesised and characterised by using several spectral and analytical techniques. The antioxidant activities of these organic compounds were analysed by using HPSA, DPPH and ABTS·+ assays. Anti-inflammatory property of the synthesised derivatives was analysed by evaluating albumin denaturation inhibition abilities. Optical energy band gaps were evaluated using the Tauc plots. Computational method was used to analyse the frontier molecular orbitals of the compounds and MEP surface analysis was used to identify the nucleophilic and electrophilic attacking sites. Owing to the higher antioxidant potential the interaction of the compound 2 with the protein Tyrosinase (isolated from the bacterium, Bacillus megaterium) was investigated using detailed molecular docking and simulation methods. Compound 2 exhibited higher free radical scavenging activity, good anti-inflammatory property and found to effectively bind to the Tyrosinase protein. These derivatives have potential application in the production of improved antioxidant and anti-inflammatory agents as well as cosmeceuticals.

Isocitrate dehydrogenases (IDHs) regulate the distribution of carbon flux between the TCA cycle and glyoxylate shunt through reversible phosphorylation that influences pathogen virulence. Current studies only indicate that NADP⁺-specific IDHs (NADP-IDHs) can be phosphorylated. Whether NAD⁺-specific IDHs (NAD-IDHs) are susceptible to phosphorylation remains unknown. In this study, two NAD-IDHs and their regulation by phosphorylation from Stenotrophomonas maltophilia and Xanthomonas sacchari were characterised for the first time. Ser80 was identified by mass spectrometry as the phosphorylation site in SmIDH, which was functionally validated through site-directed mutagenesis. Acetate induction led to an approximately 78% decrease in the ratio of IDH/ICL specific enzyme activity, consistent with phosphorylation-mediated regulation. By modifying key recognition regions in XsIDH and XsAceK, the phosphorylation efficiency of XsIDH was improved, revealing evolutionary insights. It may enable further investigations for the new antibacterial drug targets in S. maltophilia and X. sacchari.

The excessive synthesis of melanin leads to skin hyperpigmentation. While tyrosinase activity inhibition has demonstrated efficacy in ameliorating hyperpigmentation, its effectiveness remains limited, and tyrosinase inhibitors may induce irritant contact dermatitis. Therefore, there is an imperative need to develop safer and more potent anti-pigmentation agents. Melanin transfer inhibition represents a novel therapeutic strategy for treating hyperpigmentation. This review systematically elucidates the complete process of melanin transfer and its underlying mechanisms. Furthermore, it provides a comprehensive analysis of natural products and small molecule compounds with melanin transfer-inhibiting capabilities, potential compounds that may exhibit anti-pigmentation effects, as well as the binding modes and structure-activity relationships (SARs) of representative compounds. The presented evidence is crucial for identifying and developing novel, highly effective anti-pigmentation medications.