Eur J Med Chem [JOURNAL]
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200 papers
Design, synthesis, and biological evaluation of a potent and selective AURKB degrader.
Piao L, Su Y, Gao Y … +9 more , Li Q, Yan K, Chen Z, Wang YD, Zhou J, Gao Y, Liu J, Chang S, Kong R
Eur J Med Chem · 2026 Jun · PMID 42263581 · Publisher ↗
Aurora kinase B (AURKB), a key component of the chromosomal passenger complex (CPC), plays a critical role in mitosis and is aberrantly expressed in various human cancers, including acute myeloid leukemia (AML), colorect...
Aurora kinase B (AURKB), a key component of the chromosomal passenger complex (CPC), plays a critical role in mitosis and is aberrantly expressed in various human cancers, including acute myeloid leukemia (AML), colorectal cancer, and non-small cell lung cancer (NSCLC). Although AURKB represents an attractive therapeutic target, the clinical translation of conventional ATP-competitive inhibitors has been hindered by poor selectivity and dose-limiting toxicity. PROTAC technology offers a promising strategy to overcome these limitations by achieving selective protein degradation. Guided by molecular docking, we herein developed a series of novel AURKB-targeting PROTACs. Among them, compounds 1 and 3 emerged as potent and highly selective AURKB degraders, exhibiting DC values in the low nanomolar range with minimal activity against AURKA. Mechanistic studies confirmed that compound 1 forms a stable ternary complex with AURKB and the E3 ligase CRBN in cells, leading to time- and ubiquitin-proteasome system (UPS)-dependent degradation. Interestingly, beyond enzymatic inhibition, targeted degradation of AURKB also led to the downregulation of other CPC components (borealin, INCENP, survivin) and the transcription factor YY1, which are stabilized through direct interaction with AURKB. In addition, compound 1 suppressed proliferation across a panel of cancer cell lines, induced G2/M phase arrest, and triggered apoptosis. Together, this study presents a highly potent and selective AURKB degrader, offering a valuable chemical probe for studying CPC biology and a promising lead for cancer therapy.
Converting FGFR inhibitors into selective covalent molecular glue degraders via transposable gluing handles.
Cao X, Huang X, Song C … +5 more , Shi S, Zhu Y, Zheng L, Liang G, Chen L
Eur J Med Chem · 2026 Jun · PMID 42258945 · Publisher ↗
Molecular glue degraders (MGDs) have emerged as a transformative therapeutic modality, offering the potential to deplete undruggable or pathogenic proteins. However, the rational design of MGDs remains inherently challen...
Molecular glue degraders (MGDs) have emerged as a transformative therapeutic modality, offering the potential to deplete undruggable or pathogenic proteins. However, the rational design of MGDs remains inherently challenging compared to traditional heterobifunctional degraders. Recently, the implementation of transposable chemical gluing handles has provided an efficient approach to convert established protein-targeting ligands into target-specific MGDs. In this study, by incorporating diverse molecular glue handles and amino acid-based degrons into the solvent-exposed exit vectors of infigratinib, we synthesized a library of 30 candidate MGDs. Preliminary screening and subsequent lead optimization identified LC-MG-5 and LC-MG-10 as highly efficient degraders of FGFR2. In cellular models, both compounds demonstrated potent suppression of FGFR2-mediated signaling pathways. Mechanistic investigations revealed that the covalent engagement of the gluing handle is a critical determinant for successful proteasomal degradation of FGFR2. This work provides a framework for the rational transformation of kinase inhibitors into covalent molecular glue degraders, underscoring the potential of FGFR degradation as a next-generation precision medicine strategy for FGFR2-driven malignancies.
Design, synthesis, and evaluation of novel thieno[2,3-b]pyridine derivatives as DRAK2 inhibitors.
Shu Y, Zhang B, Zhang Y … +10 more , Zhang X, Xu H, Li R, Liu Y, Zhang Y, Xiong M, Tang J, Lu Y, Li J, Yang F
Eur J Med Chem · 2026 Jun · PMID 42251818 · Publisher ↗
DRAK2 (STK17B), a serine/threonine kinase, functions as a positive regulator of apoptosis. Despite its therapeutic potential, pharmacological inhibition of DRAK2 remains underexplored. To address this gap, we leveraged t...
DRAK2 (STK17B), a serine/threonine kinase, functions as a positive regulator of apoptosis. Despite its therapeutic potential, pharmacological inhibition of DRAK2 remains underexplored. To address this gap, we leveraged the previously disclosed small-molecule DRAK2 inhibitor 22b as a chemical starting point and designed, synthesized, and evaluated a novel series of thieno[2,3-b]pyridine derivatives. Through systematic structure-activity relationship (SAR) analysis, compound I14 was identified as a lead DRAK2 inhibitor with favorable bioactivity. It exhibited improved DRAK2 inhibitory potency (IC = 198.5 nM) relative to the reference compound 22b; enhanced glucose-stimulated insulin secretion (GSIS) in mouse pancreatic islets by 1.86-fold (low dose) and 1.72-fold (high dose); elevated mitochondrial membrane potential (MMP) in INS-1E cells by 1.08-fold and 1.10-fold, respectively; and mitigated palmitic acid (PA)-induced MMP impairment and apoptosis. In vivo, I14 significantly improved glucose tolerance in an oral glucose tolerance test (OGTT). Mechanistically, I14 exerted its efficacy through modulation of the DRAK2-ULK1 signaling axis which was well established in our previous study. Molecular docking analyses further supported its target engagement, revealing stable hydrogen-bond interactions with Ala113 and Lys37 within the DRAK2 ATP-binding pocket. Collectively, these findings identify I14 as the first orally efficacious, mechanism-validated DRAK2 inhibitor with translational relevance for type 2 diabetes (T2D) therapy.
Recent advancements in 1,2,3-triazole-based derivatives as antidiabetic agents: Synthesis and biological insights.
Moura NMM, Coutinho V, Abu-Orabi ST … +1 more , Cavaleiro JAS
Eur J Med Chem · 2026 Jun · PMID 42250493 · Publisher ↗
Type-2 diabetes mellitus remains a significant global health challenge, pointing to a continuous search for more effective and selective therapeutic agents. The 1,2,3-triazole scaffolds have been highlighted as potential...
Type-2 diabetes mellitus remains a significant global health challenge, pointing to a continuous search for more effective and selective therapeutic agents. The 1,2,3-triazole scaffolds have been highlighted as potential pharmacophores in this field over the past decade owing to their high metabolic stability, favorable electronic properties, and versatile capacity to participate in hydrogen bonding and π-stacking interactions within enzymatic binding sites. This review provides a comprehensive and critical analysis of the advancements during the last ten years in 1,2,3-triazole-based antidiabetic research in the synthesis and biological evaluation of new derivatives as potential drugs. Such new derivatives are based on compounds synthesized via copper-catalyzed azide-alkyne cycloaddition (CuAAC), a methodology which allows the synthesis of structurally diverse libraries of triazole-based targets.
IMD-0354 optimization generates potent colistin adjuvants with in vivo activity and reduced eukaryotic toxicity.
Cowart LJ, Nemeth AM, Jania LA … +7 more , Overly M, Ellis CF, Koller BH, Melander RJ, Doi Y, Ernst RK, Melander C
Eur J Med Chem · 2026 Jun · PMID 42248056 · Publisher ↗
The development of novel therapeutic approaches to combat infections that stem from extensively drug-resistant (XDR) gram-negative bacteria remains an area of significant unmet need. One such approach is the use of antib...
The development of novel therapeutic approaches to combat infections that stem from extensively drug-resistant (XDR) gram-negative bacteria remains an area of significant unmet need. One such approach is the use of antibiotic adjuvants. Currently, colistin (polymyxin E) is used as the antibiotic of last resort for the treatment of XDR gram-negative bacterial infections. However, resistance to this antibiotic is on the rise. We previously reported that IMD-0354 (an IκB kinase-β inhibitor) and related salicylanilide adjuvants overcome colistin resistance in several gram-negative pathogens. However, this scaffold exhibits unfavorable eukaryotic toxicity, thought to arise from the salicyl moiety. Herein, we investigate the structure-activity relationship (SAR) of second-generation m-hydroxybenzanilide analogs of IMD-0354, to uncover compounds with reduced eukaryotic toxicity and IκB kinase-β inhibitory properties, while maintaining colistin adjuvant activity. We have identified new leads that lower the colistin minimum inhibitory concentration (MIC) upwards of 2048-fold against highly colistin-resistant Acinetobacter baumannii and Klebsiella pneumoniae. In particular, NDM-622 exhibits reduced HepG2 toxicity compared to IMD-0354, with an IC of 125 ± 8.0 μM (59.4 ± 3.8 μg/mL) and a therapeutic index of ≥50. In a murine peritonitis model using a highly a colistin-resistant K. pneumoniae strain, NDM-622 and colistin together effect a decrease in colony forming units (CFUs) compared to treatment with colistin alone or vehicle controls. Preliminary mechanism-of-action (MoA) studies suggest that m-hydroxybenzanilides, including NDM-622, likely act via a mechanism distinct from IMD-0354.
Design, synthesis and anti-AML activity of guanidyl stapled peptide targeting MLAA-34/MST3 interaction.
Chao J, Shen Y, Gao S … +8 more , Shen H, Zhang S, Xu Y, Shi Y, Cong W, Niu F, Li X, Chen S
Eur J Med Chem · 2026 Jun · PMID 42248055 · Publisher ↗
Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy, where drug resistance and systemic toxicities remain major clinical challenges. Recently, MLAA-34 has emerged as a promising anti-AML targe...
Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy, where drug resistance and systemic toxicities remain major clinical challenges. Recently, MLAA-34 has emerged as a promising anti-AML target that interacts with the MST3 protein. Herein, based on the binding epitope of the MST3 protein, we established a computer-aided rational design workflow to engineer an optimized 18-residue linear baseline peptide (MST3-0), and subsequently developed a series of all-hydrocarbon and guanidyl-stapled analogues. Among these, the optimal guanidyl-stapled peptide, MST3-9-3d, synthesized via our solid-phase side-chain guanidyl-construction strategy, exhibited a markedly increased α-helical content and enhanced proteolytic stability against chymotrypsin. Crucially, isothermal titration calorimetry (ITC) confirmed that MST3-9-3d possessed the highest binding affinity (K = 4.69 ± 0.69 μM) to MLAA-34. Benefiting from the introduced guanidyl groups, MST3-9-3d displayed dramatically improved cellular uptake and potent anti-proliferative activity against OCI-AML3 cells (IC = 22.37 μM), outperforming both its linear and hydrocarbon-stapled counterparts. Furthermore, MST3-9-3d demonstrated favorable biocompatibility with negligible hemolytic toxicity and high selectivity over normal bone marrow-derived macrophages. In vivo pharmacokinetic evaluation in mice revealed a prolonged half-life (T = 3.52 h) and sustained systemic exposure. Molecular dynamics simulations unveiled that the guanidyl staple not only rigidified the peptide conformation but also directly engaged in target recognition by forming extra intermolecular hydrogen bonds. Together, these findings highlight MST3-9-3d as a highly promising lead inhibitor targeting the MLAA-34/MST3 interaction for AML therapy.
Dual-target antibacterial agents: Bridging molecular relationships to synergistic mechanisms.
Li YZ, Wang SX, Liang JH
Eur J Med Chem · 2026 Jun · PMID 42241778 · Publisher ↗
Antimicrobial resistance (AMR) has emerged as a critical global health crisis, exacerbated by the stagnation of novel antibiotic discovery and declining efficacy of existing clinical agents. Dual-target antibacterial str...
Antimicrobial resistance (AMR) has emerged as a critical global health crisis, exacerbated by the stagnation of novel antibiotic discovery and declining efficacy of existing clinical agents. Dual-target antibacterial strategy has emerged as a promising approach to address this challenge. This review systematically summarizes the cutting-edge advances in dual-target antibacterial agents, covering their core design strategies, structure-activity relationships, preclinical and clinical efficacy/safety profiles, and dual-target mechanism validation. We classify these agents by key target combinations, analyze representative candidates with potent activity against drug-resistant pathogens and reduced resistance development, and identify major translational challenges including suboptimal pharmacokinetics, imbalanced target potency, and preexisting resistance. Notably, we highlight that rational designs based on classical pharmacophores enable novel target engagement, and further discuss non-classical peptide-based agents that achieve exceptional anti-resistant efficacy and undetectable resistance emergence. In conclusion, dual-target agents represent a paradigm shift in combating AMR, offering superior efficacy and lower resistance risk than traditional approaches. The integration of novel targets with artificial intelligence-driven discovery platforms will further accelerate the development of these innovative therapeutics.
Design, synthesis, and biological evaluation of novel ICA-II derivatives as anti-hepatocellular carcinoma agents targeting EGFR.
Kou W, Wang S, Yan Q … +6 more , Zhao Y, Ma X, Sun P, Liu Q, Liu D, Song S
Eur J Med Chem · 2026 May · PMID 42241777 · Publisher ↗
The urgent need for new hepatocellular carcinoma (HCC) therapies has driven the exploration of natural product scaffolds. In this context, Icariside II (ICA-II) presents a valuable starting point for structural optimizat...
The urgent need for new hepatocellular carcinoma (HCC) therapies has driven the exploration of natural product scaffolds. In this context, Icariside II (ICA-II) presents a valuable starting point for structural optimization. Applying bioisosterism and pharmacophore hybridization, we synthesized a series of 26 nitrogen heterocycle-modified ICA-II derivatives. Subsequent structure-activity relationship (SAR) profiling highlighted compound 3b as the most potent analog. This molecule exhibited robust anti-proliferative activity across multiple HCC cell lines (HepG2, Hep3B, and Huh7), surpassing both the parent ICA-II and the positive control Sorafenib. To uncover its primary target, we integrated network pharmacology with molecular docking and dynamics simulations. This computational prediction was further supported by cellular thermal shift assays and EGFR enzymatic inhibition studies, suggesting EGFR as a potential target of 3b. Compound 3b suppressed EGFR phosphorylation and inhibited the downstream PI3K/Akt signaling pathway. This blockade precipitates a profound intracellular accumulation of reactive oxygen species ultimately driving the cancer cells into caspase-dependent apoptosis. Animal studies using a Huh7 xenograft model further corroborated its therapeutic potential. Compound 3b administration markedly suppressed tumor growth without significant body weight loss or obvious histopathological abnormalities in major organs under the tested conditions, notably outperforming the clinically approved agent Icaritin. Preliminary pharmacokinetic studies further demonstrated that 3b achieved robust systemic exposure and a prolonged retention time following intravenous administration. Overall, our work provides a successful structural optimization rationale for ICA-II and advances 3b as a safe, EGFR-modulating lead compound for HCC intervention.
PyMACS: A python-based automation suite for GROMACS molecular dynamics setup, simulation, and analysis.
Schulz JM, Reynolds RC, Schürer SC
Eur J Med Chem · 2026 Jun · PMID 42241776 · Publisher ↗
Molecular-dynamics (MD) simulations provide atom-level insight into biomolecular motion and are widely used to complement structure-guided drug discovery, ligand optimization, and mechanistic structural biology. However,...
Molecular-dynamics (MD) simulations provide atom-level insight into biomolecular motion and are widely used to complement structure-guided drug discovery, ligand optimization, and mechanistic structural biology. However, reproducible MD remains technically challenging because users must coordinate structure cleanup, force-field-compatible topology generation, ligand parameterization, solvation, ionization, energy minimization, equilibration, production simulation, trajectory processing, and downstream interpretation; errors at any stage can compromise results and discourage non-expert users. Here, we present PyMACS, an open-source Python automation framework for GROMACS-based molecular dynamics using the CHARMM36 or CHARMM36/LJ-PME biomolecular force fields together with CGenFF-compatible small-molecule parameterization. PyMACS accepts common structural input formats, including PDB, CIF, and mmCIF files, and is designed to operate on a broad range of user-supplied biomolecular systems rather than being restricted to a single target class or experimentally resolved protein-ligand complexes. Compatible inputs include experimental structures, docked or model-derived complexes, computationally predicted biomolecular assemblies, apo proteins, protein-ligand systems, cofactor-containing complexes, peptide-protein assemblies, protein-protein complexes, RNA-, DNA-, and mixed nucleic-acid-protein systems for setup and simulation workflows when residue naming and CHARMM/GROMACS topology generation support the input, and PROTAC or other ternary-complex models when force-field compatibility requirements are met. The pipeline automates structure preparation, ligand and component handling, GROMACS topology generation, system assembly, solvation, ionization, equilibration, production MD, checkpoint-aware execution, and post-simulation analysis. PyMACS also converts completed trajectories into interpretable outputs including RMSD, RMSF, radius of gyration, ligand-stability metrics, residue-contact summaries, interaction-network visualizations, CSV exports, and report-ready figures. Designed for both interactive novice use and headless reproducible execution, PyMACS lowers the barrier to rigorous MD simulation while preserving configurable control over scientific parameters, computational resources, and analysis thresholds. By integrating setup, simulation, analysis, and visualization into a transparent workflow, PyMACS enables medicinal chemists and structural biology researchers to evaluate candidate binding hypotheses, compare biomolecular systems, and generate reproducible MD-derived evidence with substantially reduced manual overhead.
Design, synthesis and evaluation of an uncharged broad spectrum quinoline-oxime hybrid for the reactivation of nerve agent-inhibited human acetylcholinesterase.
De Sousa J, Calas AG, De La Mora E … +16 more , Landry C, Hanak AS, Maryan-Instone A, Gastellier AJ, Coisne C, Courageux C, Hachani J, Gosselet F, Dehouck MP, Rousseau C, Timperley CM, Weik M, Nachon F, Brown RCD, Baati R, Dias J
Eur J Med Chem · 2026 Jun · PMID 42241775 · Publisher ↗
Organophosphorus nerve agents exert their acute toxicity by irreversibly inhibiting acetylcholinesterase (AChE), yet currently deployed oxime reactivators exhibit limited efficacy in the central nervous system due to poo...
Organophosphorus nerve agents exert their acute toxicity by irreversibly inhibiting acetylcholinesterase (AChE), yet currently deployed oxime reactivators exhibit limited efficacy in the central nervous system due to poor blood-brain barrier (BBB) penetration. Addressing this limitation remains a critical challenge in the treatment of nerve agent exposure. We report the design, synthesis, and evaluation of JDS364, an uncharged hybrid oxime reactivator combining a quinoline-based peripheral site ligand with a 3-hydroxypyridinealdoxime nucleophile. In vitro studies using human AChE inhibited by surrogates of G- and V-series nerve agents demonstrated that JDS364 possesses broad-spectrum reactivation activity, notably achieving a 300-fold increase in reactivation efficiency (k) over the clinical benchmark obidoxime against tabun-like inhibited hAChE. Evaluation in a human in vitro BBB co-culture model revealed that JDS364 exhibits high permeability, significantly outperforming clinically used quaternary oximes and exceeding the flux of earlier-generation uncharged hybrids. Ex vivo functional profiling studies in mice confirmed rapid systemic availability and significant protection against paraoxon challenge (Protective Index = 6.7 when combined with atropine), though a narrower therapeutic window was observed compared to clinical standards. X-ray crystallographic analysis of JDS364 bound to human AChE uncovered ligand-induced conformational plasticity, providing the first structural evidence of an opening of a "backdoor" via Tyr449 rearrangement in the 20 Å deep active site gorge. This confirms the hypothesis of enzyme "breathing" motions and validates alternative diffusion pathways for reactivation. These findings establish JDS364 as a mechanistically significant, CNS-accessible lead that defines a new structural paradigm for the development of next-generation countermeasures.
Leveraging multitargeting BChE-MAO B inhibitors against microglia-related neuroinflammation: in vitro biological evaluation, structure-activity relationships, drug-like properties, and X-ray crystal complexes.
Rullo M, La Spada G, Brazzolotto X … +14 more , Marchese S, El Idrissi IG, Miciaccia M, Colella M, Brea JM, Macchia E, Loza MI, Gottinger A, Scilimati A, Perrone MG, Stefanachi A, Binda C, Leonetti F, Pisani L
Eur J Med Chem · 2026 May · PMID 42241774 · Publisher ↗
Neuroinflammatory process is a key factor in multifaceted neurodegenerative disorders, as proved by the increased levels of pro-inflammatory mediators, primarily released by microglia and astrocytes. Following a multitar...
Neuroinflammatory process is a key factor in multifaceted neurodegenerative disorders, as proved by the increased levels of pro-inflammatory mediators, primarily released by microglia and astrocytes. Following a multitarget strategy, we aimed at identifying dual inhibitors of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO B). Both enzymes emerged as promising targets for tuning the inflammatory response within the central nervous system (CNS). Here we describe the synthesis, in vitro biological evaluation, and drug-likeness characterization of a series of 16 methoxy-bearing coumarin derivatives. Among them, compound 9 behaved as a well-balanced dual-acting inhibitor (hBChE, IC = 557 nM; hMAO B, IC = 142 nM) capable of mitigating interleukin-6 release from stimulated human microglia clone 3 (HMC3) cells in a dose-dependent manner and of counteracting 6-hydroxydopamine (6-OHDA) toxicity in SH-SY5Y neuroblastoma cell lines. Moreover, X-ray crystal structures of 9 in both hBChE and hMAO B were solved at 2.36 Å and 1.60 Å resolution, respectively.
Cephalosporins are potent SARS-CoV-2 main protease inhibitors.
Muntean DG, Treyde W, Laczi D … +7 more , Laidlaw SM, Salah E, Choudhry H, Carroll MW, Duarte F, Schofield CJ, Brewitz L
Eur J Med Chem · 2026 May · PMID 42235189 · Publisher ↗
The SARS-CoV-2 main protease (M) plays a pivotal role in viral replication and is a validated therapeutic target. Previous work has revealed that derivatives of clinically used penicillin antibiotics can inhibit Min vitr...
The SARS-CoV-2 main protease (M) plays a pivotal role in viral replication and is a validated therapeutic target. Previous work has revealed that derivatives of clinically used penicillin antibiotics can inhibit Min vitro through non-covalent binding at the active site or formation of stable acyl-enzyme complexes via reaction of the nucleophilic Cys145 with the penicillin β-lactam ring. Here we demonstrate that cephalosporin derivatives are substantially more potent inhibitors of isolated M than the reported penicillin derivatives. Structure-activity relationship and computational studies reveal the importance of appropriate cephalosporin C3 substitution in modulating inhibition potency and mechanism, with both covalent reaction with Cys145 and non-covalent active site binding being observed. Cephalosporin derivatives also show potential for inhibiting SARS-CoV-2 replication in infected cells. The combined results imply that the cephalosporin scaffold may be of use for development of antiviral drugs targeting the SARS-CoV-2 proteases and, by implication, other nucleophilic cysteine proteases. They further highlight the potential of bicyclic β-lactams for therapeutic applications beyond their established use as antibiotics inhibiting bacterial nucleophilic serine transpeptidases.
Discovery of novel 20S-protopanaxadiol derivatives in alleviating sepsis-associated liver injury by modulating p65/p50 activity.
Hao Z, Luan X, Mi X … +9 more , Zhang C, Ji N, Wang Y, Hu H, Chen J, Du Y, Pei X, Yu H, Yang G
Eur J Med Chem · 2026 Jun · PMID 42235188 · Publisher ↗
Sepsis-associated acute liver injury (SALI) is a common and severe complication of sepsis, contributing directly to disease progression and increased mortality. In this study, a series of 20S-protopanaxadiol (20S-PPD) de...
Sepsis-associated acute liver injury (SALI) is a common and severe complication of sepsis, contributing directly to disease progression and increased mortality. In this study, a series of 20S-protopanaxadiol (20S-PPD) derivatives with anti-inflammatory properties were designed and synthesized. Structure-activity relationship (SAR) analysis at key sites, based on nitric oxide (NO) inhibition assays, identified 9a as the most potent anti-inflammatory derivative. Remarkably, 9a alleviated SALI in a concentration-dependent manner, demonstrating superior efficacy to the glucocorticoid drug hydrocortisone sodium succinate. This protective effect was achieved by suppressing abnormal activation of the NF-κB and MAPK signaling pathways, without activating glucocorticoid receptor (GR) signaling. The apparent paradox between the effect of 9a on IκB degradation and its anti-inflammatory activity prompted further investigation. Pull-down assays further identified the p65-p50 heterodimer as a target of 9a. Molecular docking and cellular thermal shift assay (CETSA) confirmed that 9a bound to the p50 subunit, impairing the DNA-binding capacity of the p65-p50 heterodimer and consequently exerting anti-inflammatory activity. This study provides detailed SAR insights into 20S-PPD derivatives for anti-inflammatory drug development and offers new perspectives on their mechanism of action in mitigating SALI.
Update on inhibitors of 17β-hydroxysteroid dehydrogenase type 1: Reports on structure-function relationship, docking and molecular dynamic simulations.
Martinović M, Sedlacek Miskerikova M, Novak J … +1 more , Rižner TL
Eur J Med Chem · 2026 May · PMID 42235187 · Publisher ↗
17β-Hydroxysteroid dehydrogenase type 1 (HSD17B1) is a crucial enzyme in the family of 17β-hydroxysteroid dehydrogenases, serving as one of the primary activators of estrogens. Its physiological significance is highlight...
17β-Hydroxysteroid dehydrogenase type 1 (HSD17B1) is a crucial enzyme in the family of 17β-hydroxysteroid dehydrogenases, serving as one of the primary activators of estrogens. Its physiological significance is highlighted by its involvement in a wide range of estrogen-related conditions, including benign diseases and hormone-dependent cancers. Consequently, the development of selective inhibitors for HSD17B1 has attracted sustained interest for several decades. Numerous lead compounds have been identified, and various strategies for reversible inhibition have been explored, reflecting the complexity of modulating estrogen biosynthesis without causing unwanted side effects. This review focuses on advances made since 2018, highlighting how research has continued to refine existing leads by improving potency, enhancing metabolic stability, and minimising estrogenic activity. In addition to optimising known scaffolds, novel directions have emerged, such as designing compounds capable of dual targeting across different enzymes involved in estrogen formation and introducing new structural scaffolds. The inhibitor candidates identified in recent years can be grouped into five distinct subcategories, each representing a different approach to reversible HSD17B1 inhibition. To provide a comparative perspective, representative compounds from these categories have been evaluated using molecular dynamics simulations, offering insight into binding behaviour and mechanistic differences.
Evolution of PSMA-GRPr heterobivalent radiolabeled conjugates for the diagnosis and therapy of prostate cancer.
Grigoriev GP, Beloglazkina EK, Petrov SA
Eur J Med Chem · 2026 Jun · PMID 42235186 · Publisher ↗
This review focuses on heterobivalent conjugates with therapeutic and diagnostic action for targeted delivery to prostate cancer (PC) cells. All currently published studies on this topic, identified in the literature by...
This review focuses on heterobivalent conjugates with therapeutic and diagnostic action for targeted delivery to prostate cancer (PC) cells. All currently published studies on this topic, identified in the literature by February 2026, were analyzed in this review. The review begins with an introduction to targeted delivery and the development of the heterobivalent conjugate concept. Primary attention was paid to small-molecule conjugates targeting both prostate-specific membrane antigen (PSMA) and gastrin-releasing receptor (GRPr), as these two receptors are the most common targets in the development of heterobivalent (HBV) radiopharmaceuticals for the treatment of PC. A comparison of synthetic schemes and chemical parameters, analytical methods, in vitro and in vivo biological assay data, and radiochemical testing was analyzed.
A critical review of quinoline hybrids as privileged scaffolds for anti-malarial therapy.
Zhuang Y, Cheng Y, Chen L … +1 more , Cai F
Eur J Med Chem · 2026 May · PMID 42235185 · Publisher ↗
Malaria remains a life-threatening parasitic disease of global concern, with the emergence and spread of drug-resistant Plasmodium strains necessitating the development of novel, potent, and safe anti-malarial agents. As...
Malaria remains a life-threatening parasitic disease of global concern, with the emergence and spread of drug-resistant Plasmodium strains necessitating the development of novel, potent, and safe anti-malarial agents. As a privileged pharmacophore with inherent anti-malarial potential, quinoline exerts its anti-malarial effects primarily by inhibiting hemozoin crystallization, interfering with parasite metabolic pathways, disrupting DNA replication and protein synthesis, and targeting key enzymes involved in Plasmodium survival. Of note, quinoline hybrids exhibit prominent advantages, including potent antimalarial activity against both drug-sensitive and drug-resistant Plasmodium strains, structural versatility enabling rational modification, and tunable pharmacokinetic properties, making them superior to single quinoline derivatives in combating malaria and overcoming drug resistance. This critical review comprehensively delineates the research advances of quinoline hybrids as potent antimalarial agents from 2020 to the present, with a particular focus on their in vitro antiplasmodial and in vivo antimalarial therapeutic potential against various Plasmodium strains (including drug-resistant isolates). Furthermore, the structure-activity relationships (SARs) of these quinoline hybrids are systematically deciphered, and the molecular mechanisms are also discussed. Finally, the translational therapeutic prospects and future research directions of quinoline hybrids are prospectively discussed, offering valuable insights for the rational design and optimization of next-generation antimalarial candidates.
SBA-15 nanostructures enable tumor-selective delivery of PhSn with enhanced anticancer activity in melanoma models.
Edeler D, Bovan D, Krajnović T … +7 more , Ilić J, Dunđerović D, Kaluđerović MR, Antonijević MR, Mijatović S, Maksimović-Ivanić D, Kaluđerović GN
Eur J Med Chem · 2026 May · PMID 42235184 · Publisher ↗
Alkylarylorganotin compounds, PhHexSn (n = 0-4), were prepared, characterized and immobilized into mesoporous nanostructured silica SBA-15. SBA-15 loaded with PhSn (SBA-15|PhSn) showed markedly enhanced antiproliferative...
Alkylarylorganotin compounds, PhHexSn (n = 0-4), were prepared, characterized and immobilized into mesoporous nanostructured silica SBA-15. SBA-15 loaded with PhSn (SBA-15|PhSn) showed markedly enhanced antiproliferative activity against B16 and A375 melanoma cells with a >50-fold increase in potency in comparison to its organotin counterpart, demonstrating that SBA-15 significantly enhances the antitumor activity of PhSn. Moreover, SBA-15 increased selectivity toward cancer cells, while free PhSn affected the viability of peritoneal exudate cells (PECs) as well as primary cell line IMLEC. Both free and immobilized PhSn suppressed the division rate of melanoma cells along with an activation of Bax and Bim mediated proapoptotic signaling pathway, supported by molecular docking studies, leading to caspase-dependent apoptosis. A significant reduction in tumor size in melanoma syngeneic model induced by s.c. inoculation of B16 cells in C57BL/6 mice revealed superior therapeutic performance of immobilized tetraphenyltin(IV) in comparison to the free compound with no observable systemic toxicity, in contrast to the severe side effects observed in animals treated with CP (cisplatin). Pharmacokinetic modeling further highlights the significant improvement in solubility, bioavailability, and tissue selectivity conferred by SBA-15 immobilization.
Multivalent C2-alkyl trihydroxypiperidine architectures modulate β-glucocerebrosidase activity.
Buco F, Clemente F, Cardona F … +6 more , Morrone A, Paoli P, Moya SE, Goti A, Matassini C, Marradi M
Eur J Med Chem · 2026 May · PMID 42229236 · Publisher ↗
Multivalent systems based on C2-alkylated (3R,4R,5R)-3,4,5-trihydroxypiperidines, members of the iminosugar family, were developed as modulators of the lysosomal enzyme β-glucocerebrosidase (GCase), whose deficiency caus...
Multivalent systems based on C2-alkylated (3R,4R,5R)-3,4,5-trihydroxypiperidines, members of the iminosugar family, were developed as modulators of the lysosomal enzyme β-glucocerebrosidase (GCase), whose deficiency causes Gaucher disease and is also related to Parkinson disease. The iminosugar units were successfully multimerized onto tri- and tetrapodal scaffolds and gold nanoparticles, enabling a systematic investigation of the multivalent effects. Both architectures exhibited a marked enhancement in inhibitory potency compared to a suitable monovalent reference compound, proving a strong multivalent effect. However, while tri- and tetravalent compounds primarily act as enzyme inhibitors in cellular assays, gold nanoparticle-based systems retain a productive chaperone window, promoting mutant N370S GCase rescue in Gaucher patient-derived fibroblasts by up to 1.7-fold at 100 nM, without detectable cytotoxicity. Overall, these findings highlight the critical role of scaffold organization in balancing enzyme inhibition and functional rescue in the design of multivalent pharmacological chaperones for Gaucher disease.
Discovery of 1,3-disubstituted indole derivatives as ATP-competitive inhibitors of sphingosine kinase for tumor therapy.
Zhang M, Huo Y, Song Y … +5 more , Li L, Meng M, Guo J, Cao F, Yang K
Eur J Med Chem · 2026 May · PMID 42229235 · Publisher ↗
Targeting Sphingosine kinase (SphK1/2) has become a novel strategy for the treatment of cancer. However, potent ATP competitive inhibitors are rare. Herein, a series of novel SphK1 and SphK2 inhibitors were identified th...
Targeting Sphingosine kinase (SphK1/2) has become a novel strategy for the treatment of cancer. However, potent ATP competitive inhibitors are rare. Herein, a series of novel SphK1 and SphK2 inhibitors were identified through virtual screening and structural optimization. The structure-activity relationship revealed compound 9d had excellent inhibitory activity and selectivity on SphK1. 9d can increase the level of Sph while reducing the content of S1P in vivo and in vitro. Moreover, 9d demonstrated anti-tumor effect on various cell lines and mouse models. In addition, another compound 6a was found to have good inhibitory activity and selectivity on SphK2 and showed potent anti-proliferative activity on tumor cells. It can be studied as an inhibitor of SphK2 in the future.
Novel aromatic amide Pan-PPAR agonists for dual amelioration of hepatic steatosis and islet dysfunction by promoting cholesterol efflux in the KKAy diabetic mice.
Sheng R, Zhang Y, Wang J … +12 more , Yang G, Jiang W, Ju C, Li S, Wang C, Zhang J, Lei L, Wei X, Liu T, Liu C, Xu Y, Si S
Eur J Med Chem · 2026 May · PMID 42229234 · Publisher ↗
Cholesterol metabolism disorders are a major contributor to type 2 diabetes mellitus (T2DM). Cholesterol accumulation in the liver exacerbates insulin resistance, while cholesterol overload in the pancreatic islets impai...
Cholesterol metabolism disorders are a major contributor to type 2 diabetes mellitus (T2DM). Cholesterol accumulation in the liver exacerbates insulin resistance, while cholesterol overload in the pancreatic islets impairs insulin secretion. Peroxisome proliferator activated receptors (PPARs) are considered potential therapeutic targets for cholesterol regulation. Herein, we report a series of novel aromatic amide derivatives as pan-PPAR agonists. Among them, compound 15a exhibited potent and well balanced pan-PPAR agonistic activity and significantly upregulated the expression of ATP binding cassette transporter A1 (ABCA1), a PPAR target gene involved in cholesterol efflux. In a high fat and high sucrose diet induced KKAy diabetic mouse model, 15a markedly reduced plasma cholesterol levels, hepatic cholesterol accumulation, and islet cholesterol deposition. It also demonstrated favorable regulation of glucolipid metabolism, leading to pronounced alleviation of hepatic steatosis and islet dysfunction, while avoiding the weight gain and adiposity side effects associated with PPARγ agonists. SPR experiments demonstrated that 15a interacts with the ligand binding domains (LBDs) of all three PPAR subtypes. Molecular docking and single point mutation assays of key residues confirmed that 15a likely exerts its pan PPAR agonist activity by stabilizing helix 3 of the three PPAR subtypes. Furthermore, 15a exhibits improved pharmacokinetic properties and a favorable safety profile compared to the lead compound. In summary, this study demonstrates that compound 15a significantly ameliorates hepatic steatosis and islet dysfunction associated with T2DM by regulating cholesterol metabolism disorders along the liver-islet axis, highlighting its strong potential for treating hepatic lipid accumulation and T2DM related islet dysfunction.
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