Yao X, Han X, Li Z
… +8 more, Gao W, Yu B, Chen X, Feng H, Song Y, Xiong J, Chen Y, Zhuang T
Eur J Med Chem
· 2026 Jun · PMID 42335716
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Neuropathic pain is a global health problem, affecting approximately 7%-10% of the population worldwide. In recent years, targeting glycine transporter 2 (GlyT2) has emerged as a promising strategy for the treatment of n...Neuropathic pain is a global health problem, affecting approximately 7%-10% of the population worldwide. In recent years, targeting glycine transporter 2 (GlyT2) has emerged as a promising strategy for the treatment of neuropathic pain, as it enhances glycinergic neurotransmission and strengthens inhibitory control of nociceptive signal transmission. A series of N-(alkylpiperidinyl) substituted benzamides were designed, synthesized, and evaluated as potential GlyT2 inhibitors, and their binding affinities were assessed in vitro by surface plasmon resonance assay. Compound 14 was found to have potent affinity, with a K value of 23.7 nM. In mice, 14 exhibited robust antinociceptive effects in the formalin test (ED = 30.5 mg/kg), abdominal contraction (ED = 26.0 mg/kg) test, and paclitaxel-induced neuropathic pain (ED = 12.17 mg/kg) models, with overall activity superior to the reference drug gabapentin. The antinociceptive effect of 14 was attributable to the inhibition of glycine transporters, as confirmed by combined administration of strychnine (a glycine receptor antagonist) in mice. In addition, 14 functionally inhibited GlyT2-mediated glycine uptake with an IC value of 19.4 nM. Furthermore, 14 exhibited an improved safety profile compared to gabapentin, notably with reduced sedative effects and less impairment of motor coordination. Compound 14 also exhibited favorable pharmacokinetic properties in rats. Taken together, these findings highlight 14 as a promising lead candidate for developing safer and more effective analgesics against neuropathic pain.
Zhang Y, Kan C, Ai J
… +10 more, Zhou R, Zhao Q, Gao J, Wang Y, Wu Z, Qin X, Ma J, Yuan B, Liu M, Luo Q
Eur J Med Chem
· 2026 Jun · PMID 42335715
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Cyclin-dependent kinase 6 (CDK6) has been reported to exert tumor-suppressive functions through its non-enzymatic activity and promotes the degradation of the oncogenic driver EYA2. This suggests a potential strategy for...Cyclin-dependent kinase 6 (CDK6) has been reported to exert tumor-suppressive functions through its non-enzymatic activity and promotes the degradation of the oncogenic driver EYA2. This suggests a potential strategy for targeted protein degradation by exploiting endogenous protein-protein interactions. Here, we report the design and synthesis of a bifunctional small molecule, EC21, capable of simultaneously engaging CDK6 and EYA2. Structure-guided design based on the reported binding modes of palbociclib and the EYA2 inhibitor ETC-616 enabled the identification of EC21 as a lead compound. Biological studies demonstrated that EC21 effectively reduced EYA2 protein levels in breast cancer cells in a time- and concentration-dependent manner through a ubiquitin-proteasome-dependent process. Mechanistic investigations indicated that EC21 enhances the interaction between CDK6 and EYA2, thereby promoting EYA2 degradation. Functional analyses further revealed that EC21 disrupts DNA damage repair pathways and significantly suppresses breast cancer cell proliferation. Importantly, EC21 exhibited pronounced antitumor activity in a syngeneic breast cancer mouse model and reduced EYA2 protein levels in tumor tissues without apparent toxicity. Collectively, these findings demonstrate that pharmacological stabilization of the CDK6-EYA2 interaction represents a feasible strategy for inducing EYA2 degradation and provides a potential therapeutic approach for EYA2-driven breast cancer.
Xia Z, Chen Q, Feng H
… +4 more, Zhang M, Ren M, Li R, Chen C
Eur J Med Chem
· 2026 Jun · PMID 42330872
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The colony-stimulating factor 1 receptor (CSF1R) is a class III receptor tyrosine kinase that is highly expressed on the surface of macrophages. Its activation is intricately linked not only to cancer, inflammatory respo...The colony-stimulating factor 1 receptor (CSF1R) is a class III receptor tyrosine kinase that is highly expressed on the surface of macrophages. Its activation is intricately linked not only to cancer, inflammatory responses, and skeletal disorders, but also to mutations involved in neurodegeneration and skeletal anomalies. By regulating the function of tumor-associated macrophages (TAMs), CSF1R plays a pivotal role in shaping the tumor microenvironment (TME), facilitating tumor immune evasion and progression. As the critical involvement of CSF1R in various diseases continues to be elucidated, the development of CSF1R kinase inhibitors has emerged as a promising therapeutic strategy. In this review, we explore the structure characteristics, biological functions, signaling pathways of CSF1R, and its pivotal role in disease pathogenesis. We provide an overview of the advances in small-molecule CSF1R inhibitors from a medicinal chemistry perspective, including both clinical and preclinical inhibitors. Furthermore, we address future perspectives and challenges in the development of CSF1R inhibitors, offering valuable insights for ongoing research in this field.
Yao X, Zhao S, Zhang H
… +6 more, Liang G, Ma Y, Ga L, Yang H, Yang B, Zhao Y
Eur J Med Chem
· 2026 Jun · PMID 42330871
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Urea transporters (UT) serve as promising diuretic targets, as their inhibitors selectively promote urea excretion without disturbing electrolyte balance, making them suitable for long-term therapy. Based on the structur...Urea transporters (UT) serve as promising diuretic targets, as their inhibitors selectively promote urea excretion without disturbing electrolyte balance, making them suitable for long-term therapy. Based on the structural optimization of orally available diarylamide UT inhibitors Y02 and Y32 developed in our previous studies, compound 12f with enhanced diuretic efficiency and improved physiochemical properties was discovered in the present study. In vitro, 12f potently inhibited mouse UT-B and rat UT-B with IC value of 0.11 μM and 0.054 μM, respectively, representing 14-fold and 8-fold increases in potency over Y32, and 15-fold and 12-fold increases over Y02. Oral administration of 12f (50 and 100 mg/kg) in rats induced significant, dose-dependent diuresis with a prolonged duration of up to 24∼40 h, far exceeding the effect of Y02. Pharmacokinetic studies revealed rapid absorption (t = 0.5 h) and improved oral bioavailability (61.9%) but short plasma half-life (t = 0.989 h) of 12f, indicating that the prolonged efficacy was not directly attributed to sustained systemic exposure of the parent drug but other mechanisms which required for further investigation. Molecular docking study indicated that 12f formed multidimensional interactions with the active binding site of both UT-B and UT-A2 proteins, implying a predictable inhibitory effect to UT-A families which is beneficial for diuretic activity. Additionally, 12f exhibited 5-fold and 18-fold higher aqueous solubility than Y32 and Y02, respectively, suggesting a superior in vivo transport characteristic. Collectively, 12f is a promising orally available salt-sparing diuretic candidate targeting urea transporters, with great potential for the treatment of diseases requiring long-term diuretic therapy.
Eur J Med Chem
· 2026 Jun · PMID 42330870
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Inflammatory bowel disease (IBD) is a chronic condition characterized by recurrent intestinal ulceration. The rising global incidence of IBD in recent years has increased disease burden and highlighted the urgent need fo...Inflammatory bowel disease (IBD) is a chronic condition characterized by recurrent intestinal ulceration. The rising global incidence of IBD in recent years has increased disease burden and highlighted the urgent need for more effective and safer treatments. Small-molecule therapeutics targeting critical pathogenic pathways represent a rapidly advancing area of IBD drug development, offering the advantages of stronger target binding affinity, better specificity, and more favorable pharmacokinetic performance compared to conventional therapies. This review summarizes the progress made in IBD small-molecule drugs in the past 5 years, covering the association between related targets and IBD pathogenesis, a series of new compounds acting on distinct molecular targets, including those that have advanced recently to clinical trials as well as those demonstrating promising anti-IBD activity in preclinical studies. The targets include key proteins (BRD4, PDE4, NLRP3), kinases (JAK, RIPK, SIK, IRAK), and G protein-coupled receptors (CCR6, CXCR4). For preclinical compounds, we highlighted the key structural modification process and structure-activity relationship (SAR) studies, summarizing their anti-inflammatory and intestinal protective activities demonstrated in both in vitro and in vivo experiments. Overall, this review aims to facilitate the rational development of next-generation, more effective, and safer small-molecule therapeutics for IBD.
Bhat AA, Fuloria S, Thapa R
… +7 more, Narain K, Biswas A, Gupta K, Singh S, Biswas S, Bhatia S, Fuloria NK
Eur J Med Chem
· 2026 Jun · PMID 42330869
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Protein kinases continue to be the primary therapeutic targets in cancer therapy because they mediate proliferation, survival, angiogenesis, metastasis, and resistance to treatment. Among these scaffolds, coumarins and h...Protein kinases continue to be the primary therapeutic targets in cancer therapy because they mediate proliferation, survival, angiogenesis, metastasis, and resistance to treatment. Among these scaffolds, coumarins and hydroxycoumarins have emerged as highly versatile platforms for anticancer drug design due to their rigid benzopyran-2-one core, tunable substitution patterns, and potential for hybridization with kinase-privileged heterocycles. With an interest in medicinal chemistry, structure-activity relationships, and target binding and mechanisms, this review discusses the recently published primary literature on hydroxycoumarins and coumarin-derived derivatives developed as kinase-targeted anticancer agents. Existing evidence demonstrates that coumarin analogs have been considered against receptor tyrosine kinases (EGFR and VEGFR), survival-associated signaling nodes (PI3K/Akt/mTOR signaling), and cell cycle control kinases (CDKs and CK2). These subclasses exhibit various hydroxylation patterns and substitutions at key ring positions, linker architecture, heteroaryl fusion, and heteroaryl-aryl hybrid pharmacophores, each influencing ATP-pocket recognition, hinge-region interactions, and downstream biological responses, such as apoptosis, cell cycle arrest, and anti-migratory effects. Overall, coumarins have the potential to be used as a flexible scaffold family for the discovery of kinase-targeted anticancer drugs. However, further research is warranted to enhance the biochemical validation, optimize the selectivity, and facilitate the translational development of these compounds.
Eur J Med Chem
· 2026 Jun · PMID 42330846
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Controlled cell death (CCD) is becoming a focus as a successful practice in cancer therapy, especially when triggered specifically by light-based therapies, including photodynamic therapy (PDT) and photoactivated chemoth...Controlled cell death (CCD) is becoming a focus as a successful practice in cancer therapy, especially when triggered specifically by light-based therapies, including photodynamic therapy (PDT) and photoactivated chemotherapy (PACT). Photosensitizers (PSs) made of metal are of particular interest in this respect since the excited-state behaviour of these complexes can be rationally designed, depending on the rational design of the metal centre, ligand and oxidation state. Despite extensive literature on CCD induced by PDT, little work has given a cohesive view on metal-based PSs as inducers of particular CCD pathways. This review will highlight the decade progress in Iridium metal-based PSs that induce ferroptosis, immunogenic cell death, and pyroptosis with focus on its characteristics, mechanisms and commonalities among Iridium systems. Moreover, methods of improving biological selectivity, especially by bioconjugation of Iridium polypyridyl complexes are described. On the whole, this review is intended to gain an understanding of the logical construction of metal-based PSs to induce RCD in a controlled fashion and to stimulate the future introduction of photoactivating metal complexes to treat cancer.
Wang Q, Deng XB, Liu CL
… +5 more, Zhou J, Jin Z, Wang W, Du D, Tang YZ
Eur J Med Chem
· 2026 Jun · PMID 42323920
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Ulcerative colitis (UC) is a chronic inflammatory bowel disease with rising global prevalence that substantially impairs quality of life, yet effective therapeutic options remain limited. Non-steroidal anti-inflammatory...Ulcerative colitis (UC) is a chronic inflammatory bowel disease with rising global prevalence that substantially impairs quality of life, yet effective therapeutic options remain limited. Non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (IBU) face a therapeutic limitation in UC, as their mechanism exacerbates intestinal injury despite their significant anti-inflammatory efficacy. To overcome this clinical limitation, we designed and synthesized a series of ibuprofen-1,3,4-thiadiazole hybrids (23 compounds in total) and evaluated their anti-inflammatory activities. Notably, compound 20 at 10 mg/kg significantly ameliorated DSS-induced colitis, with efficacy superior to both the parent compound IBU (10 mg/kg) and 5-aminosalicylic acid (5-ASA, 80 mg/kg). Additionally, intervention with compound 20 also restored gut microbiota by modulating gut immunity. Detailed analyses suggested that compound 20 inhibited M1 macrophage polarization and suppressed MAPK-mediated inflammation both in vivo and in vitro. Crucially, compound 20 demonstrated favorable gastrointestinal safety profiles, in contrast to the parent compound IBU. This study underscores the potential clinical relevance of ibuprofen-1,3,4-thiadiazole hybrids as a novel therapeutic strategy for UC with improved gastrointestinal safety profiles.
Liao XM, Zhu X, Chen RK
… +5 more, Li XY, Fu H, Wu SL, Huang XY, Geng CA
Eur J Med Chem
· 2026 Jun · PMID 42320200
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Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for type 2 diabetes mellitus (T2DM). In this study, 37 cholic acid derivatives were designed and synthesized via a molecular hybridization strateg...Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for type 2 diabetes mellitus (T2DM). In this study, 37 cholic acid derivatives were designed and synthesized via a molecular hybridization strategy. Biological evaluation identified the 4-fluorophenylalanine derivative 6h as the most potent PTP1B inhibitor (IC = 32.70 μM) with a selectivity index of 7.0 over TCPTP. Structure-activity relationship (SAR) studies revealed that the 3-hydroxy-7-oxo steroid core, a free carboxylic acid group, and electron-withdrawing aromatic substituents are essential for maintaining activity. Mechanistic investigations demonstrated that 6h acts as a reversible mixed-type inhibitor of PTP1B by forming a 1:1 complex (K = 36.0 μM), and induces conformational changes as evidenced by fluorescence quenching, CD, and IR spectroscopy. Molecular docking further supported the binding mode via hydrogen bonds and hydrophobic interactions. In insulin-resistant HepG2 cells, 6h significantly promoted glucose uptake by 11.8% at 20 μM, comparable to rosiglitazone. In vivo tests, 6h dose-dependently enhanced glucose tolerance and insulin sensitivity in both normal and diabetic mice. Moreover, 6h significantly reduced random and fasting blood glucose levels in STZ-induced diabetic mice. ADMET predictions indicated favorable oral absorption, Caco-2 permeability, and low toxicity. Collectively, 6h represents a promising PTP1B selective inhibitor exerting hypoglycemic effects through enhanced insulin signaling and inhibition of gluconeogenesis, warranting further investigation as a novel anti-T2DM candidate.
Dong L, Yang J, Meng Y
… +9 more, Yang S, Pan C, Luo F, Long H, Lv S, Gong Y, Xu J, Xiong Y, Dong Y
Eur J Med Chem
· 2026 Jun · PMID 42320199
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The pathogenesis of Alzheimer's disease (AD) is closely related with glycogen synthase kinase 3β (GSK-3β) and acetylcholinesterase (AChE). Our previous work verified that GL10a displayed superior GSK-3β inhibitory and ne...The pathogenesis of Alzheimer's disease (AD) is closely related with glycogen synthase kinase 3β (GSK-3β) and acetylcholinesterase (AChE). Our previous work verified that GL10a displayed superior GSK-3β inhibitory and neuroprotective activities relative to Tideglusib. Accordingly, a molecular hybridization strategy was applied to design and synthesize a series of dual target inhibitors against GSK-3β and AChE by conjugating GL10a and carbamate fragment of Rivastigmine's pharmacophore. After in vitro evaluations, the compound AJ-4 was screened as the most remarkable compound with potent inhibitory activities against GSK-3β (IC: 4.7 nM) and AChE (IC: 2.97 μM). Meanwhile, in vitro and in vivo data revealed that the optimal compound AJ-4 with excellent enzyme selectivity could decrease amyloid precursor protein (APP) and phosphorylated Tau expressions and increase phosphorylated GSK-3β levels. With favorable pharmacokinetic characteristics and tissue distribution, AJ-4 obviously ameliorated scopolamine-induced learning and memory impairments and alleviated hippocampal neuronal injury in AD mice. In conclusion, GSK-3β/AChE dual inhibitors represent a promising strategy for developing multi-target anti-AD drugs.
Kong Z, Xie F, Xu Z
… +9 more, Zhao Y, Yu S, Zhang J, Ma R, Tang L, Wu J, Ma C, Liu ZP, Liu C
Eur J Med Chem
· 2026 Jun · PMID 42314467
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Kinases have proven to be valuable targets in anti-cancer drug discovery. In this study, we hybridized essential pharmacophores from AZD2858 and sorafenib and conducted structure-activity relationship studies, leading to...Kinases have proven to be valuable targets in anti-cancer drug discovery. In this study, we hybridized essential pharmacophores from AZD2858 and sorafenib and conducted structure-activity relationship studies, leading to the identification of a type II kinase inhibitor, compound 9, which potently inhibits GSK-3β and VEGFR2 with IC values in the nanomolar range. Western blot analysis revealed that compound 9 suppressed the phosphorylation of VEGFR2, AKT, MEK, and ERK in a dose-dependent manner. In cellular assays, compound 9 effectively inhibited CAL27 cell migration in a wound healing assay and tube formation of HUVECs, while exhibiting minimal or no antiproliferative effects on various cell lines, including MDA-MB-231, MDA-MB-468, A549, CAL27, and HUVEC cells. Moreover, compound 9 demonstrated significant antitumor efficacy in a CAL27 xenograft mouse model, showing promising potential for further development as a therapeutic agent for tongue squamous cell carcinoma.
Wang L, Zhen T, Liu H
… +4 more, Sun P, Wu X, Chen Y, Sun H
Eur J Med Chem
· 2026 Jun · PMID 42314466
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Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor, characterized by a universally dismal prognosis. For over two decades, the alkylating agent temozolomide (TMZ) has remained the cornerst...Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor, characterized by a universally dismal prognosis. For over two decades, the alkylating agent temozolomide (TMZ) has remained the cornerstone of the standard-of-care "Stupp protocol" largely owing to its unique pH-dependent activation and favorable blood-brain barrier penetration. However, the clinical efficacy of TMZ is profoundly compromised by complex intrinsic and acquired resistance mechanisms. These are primarily driven by O-methylguanine-DNA-methyltransferase (MGMT) overexpression, mismatch repair (MMR) deficiency, and hyperactive base excision repair (BER) pathways. In this review, the chemical properties and classical cytotoxic mechanisms of TMZ are comprehensively summarized, followed by a systematic exploration of emerging medicinal chemistry strategies designed to overcome this multifaceted resistance. Specifically, recent advances in circumventing MGMT-mediated repair through epigenetic modulation and targeted protein degradation are highlighted. Furthermore, we discuss the rational structural modifications of the imidazotetrazine scaffold to induce steric hindrance, alongside a paradigm shift toward rewiring cell death mechanisms-such as transitioning from DNA monomethylation to interstrand cross-linking (ICLs) and the activation of non-apoptotic pathways, including ferroptosis and autophagy. Finally, systemic interventions exploiting "BRCAness"-induced synthetic lethality via PARP inhibitors are examined, culminating in future perspectives on the integration of artificial intelligence (AI) and spatiotemporally responsive nanocarriers for the design of next-generation anti-GBM therapeutics.
Wang C, Chen P, Chen J
… +5 more, Chen H, Zhu Q, Gao S, Zheng X, Lin T
Eur J Med Chem
· 2026 Jun · PMID 42308607
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Hepatic fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components, which can potentially progress to cirrhosis and hepatocellular carcinoma. In this study, a natural product, Arenarine D,...Hepatic fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components, which can potentially progress to cirrhosis and hepatocellular carcinoma. In this study, a natural product, Arenarine D, was isolated from the endophytic fungus Pallidocercospora crystallina of Ajuga decumbens Thunb. Mechanistic studies established DYRK1B and MYH9 as potential targets of Arenarine D. Through systematic structural optimization, we obtained a series of derivatives of Arenarine D. Among them, the active derivatives 8a, 5b, 11a, and 11b demonstrated enhanced anti-fibrotic activity to varying degrees in both TGF-β1 induced hepatic stellate cells (HSCs) activation models and hepatic fibrosis models induced by bile duct ligation (BDL) and carbon tetrachloride (CCl). These results underscore the potential of Arenarine D and its derivatives as valuable candidates for developing anti-hepatic fibrosis agents.
Dai K, Zhang X, Dai J
… +13 more, Hu M, Ren J, Hu D, Tang J, Feng C, Wang F, Liu Y, Li S, Liu T, Hong Y, Yu L, Yang F, Tang W
Eur J Med Chem
· 2026 Jun · PMID 42308606
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Highly pathogenic coronaviruses pose a serious health threat. However, currently available small-molecule inhibitors (SMIs) targeting the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) spike (S) protein generall...Highly pathogenic coronaviruses pose a serious health threat. However, currently available small-molecule inhibitors (SMIs) targeting the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) spike (S) protein generally lack potency. Here, we design and synthesize a novel class of 4-(benzothiazol-2-yl)-N-substituted aniline derivatives. Distinct from most SMIs targeting viral enzymes, compound 22 potently inhibited both MERS-CoV pseudotyped and live viruses in vitro, with surface plasmon resonance (SPR) providing evidence for a direct interaction with the S protein. Alongside good solubility and metabolic stability, compound 22 exhibited in vivo proof-of-concept efficacy in hDPP4-transgenic mice by significantly reducing pulmonary viral loads. Overall, this study validates the 4-(benzothiazol-2-yl)-N-substituted aniline scaffold as an early anti-MERS-CoV pre-lead series, with compound 22 as a solid starting point for further optimization.
Liu S, Wei Y, Chen Y
… +7 more, Cheng J, Fu Y, Sun Z, Wang Y, Kang H, Liu Y, Ma Y
Eur J Med Chem
· 2026 Jun · PMID 42302665
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The spread of MDR-GNB producing both SBLs and MBLs has created an urgent unmet clinical need, as current therapies fail to address both enzyme-mediated resistance and infection-induced inflammation. Ebselen is a selenium...The spread of MDR-GNB producing both SBLs and MBLs has created an urgent unmet clinical need, as current therapies fail to address both enzyme-mediated resistance and infection-induced inflammation. Ebselen is a selenium-containing heterocyclic compound and has been identified as a novel covalent inhibitor of MBLs. Guided by structural optimization and SAR analysis, we introduced a boronic acid group as a covalent warhead targeting SBLs and finally obtained E3f. E3f exhibited potent inhibitory activity against NDM-1 (MBLs, IC = 1.8 μM) and KPC-2 (SBLs, IC = 2.6 μM) by forming covalent adducts with Cys221 of NDM-1 and Ser70 of KPC-2, respectively. In vitro antibacterial assays revealed that E3f exerts synergistic effects with antibiotics and restores the susceptibility of clinically isolated MDR-GNB to antibiotics. The MIC was reduced to as low as 1/128 of the original value. In the murine intra-abdominal infection model, combined administration of E3f and meropenem markedly reduced bacterial loads in the liver and spleen compared with meropenem monotherapy. Meanwhile, the serum levels of pro-inflammatory cytokines including TNF-α, IL-1β and IL-6 were decreased, indicating excellent in vivo efficacy. Acute toxicity tests demonstrated that E3f presents low toxicity and favorable overall safety in both Galleria mellonella larvae and mice. Furthermore, E3f effectively mitigated LPS-induced acute lung injury in mice by inhibiting ferroptosis, as evidenced by elevated FTH1 and GPX4 expression and reduced MDA levels in lung tissues. Collectively, these results confirm that E3f is a highly efficacious lead compound. Ebselen derivatives, which dually inhibit β-lactamases and produce ferroptosis-mediated anti-inflammatory activity, hold great promise as therapeutic agents against infections caused by MDR-GNB.
Zhang W, Wu W, Gao J
… +5 more, Xian J, Yao Y, Liao W, Zhang J, Wang Y
Eur J Med Chem
· 2026 Jun · PMID 42302664
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Trace amine-associated receptor 1 (TAAR1) is an important member of the trace amine receptor family that plays a crucial regulatory role in both the central and peripheral nervous systems. It is a promising therapeutic t...Trace amine-associated receptor 1 (TAAR1) is an important member of the trace amine receptor family that plays a crucial regulatory role in both the central and peripheral nervous systems. It is a promising therapeutic target for various diseases, especially psychiatric disorders. Importantly, TAAR1-targeted therapies generally exhibit favorable metabolic safety profiles and may alleviate negative and cognitive symptoms. Extensive research has demonstrated that selective TAAR1 ligands have significant pharmacological effects in preclinical models of psychiatric conditions. However, only SEP-363856 and ralmitaront have advanced into clinical trials for schizophrenia to date, highlighting the considerable opportunities that remain for the development of TAAR1-targeted therapeutics. This review provides a comprehensive overview of TAAR1's structure, biological functions, and its connection to human diseases. Additionally, it summarizes the design strategies, structure-activity relationships, and pharmacological properties of TAAR1 agonists, aiming to guide future drug development and clinical applications.
Wang K, Liu C, Shao G
… +9 more, Zhao Y, Chen X, Kong X, Hou W, Tong R, Hou T, Zhou M, Li H, Tian S
Eur J Med Chem
· 2026 Jun · PMID 42302663
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Integrated computational-experimental platforms are promising for GPCR drug discovery, but systematically connecting high-resolution structural prediction with functional validation remains challenging. Here, we apply an...Integrated computational-experimental platforms are promising for GPCR drug discovery, but systematically connecting high-resolution structural prediction with functional validation remains challenging. Here, we apply an integrated platform to discover a novel, potent antagonist targeting the P2Y receptor (P2YR), a key target in inflammatory diseases. Combining structure-based virtual screening, BPMD, all-atom molecular dynamics simulations, and cellular cAMP functional assays, our platform pinpointed Benfotiamine, an approved drug, as a nanomolar-potency P2YR antagonist (IC = 0.31 nM). Computational analyses indicated that Benfotiamine exerts a "conformational lock" to stabilize the inactive receptor and hinder Gi coupling. Subsequent CETSA and SPR experiments confirmed its direct binding to the target. Functionally, Benfotiamine exhibited therapeutic efficacy in murine models of dextran sulfate sodium-induced colitis and monosodium urate-induced gouty arthritis. Beyond presenting a promising repurposed anti-inflammatory agent, this study validates a modular and extensible computational-experimental integration platform that can be widely applied to expedite the discovery and mechanistic characterization of GPCR-targeted therapeutics.
Li Q, Van Eynde W, Van Loy T
… +10 more, Claes S, Skarka A, Andrys R, Musilek K, Pollenus E, Schlenner SM, Schols D, Voet A, Dehaen W, De Jonghe S
Eur J Med Chem
· 2026 Jun · PMID 42302662
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The human chemokine receptor 8 (CCR8) plays a role in various autoimmune disorders, such as multiple sclerosis and inflammatory bowel disease, spurring the interest in CC8 agonism as a potential therapeutic strategy. Tri...The human chemokine receptor 8 (CCR8) plays a role in various autoimmune disorders, such as multiple sclerosis and inflammatory bowel disease, spurring the interest in CC8 agonism as a potential therapeutic strategy. Triazolyl substituted phenoxybenzylpiperidine analogues have been previously synthesized and were shown to act as CCR8 agonists although with moderate potency. In this study, their structure-activity relationship was expanded by the synthesis of a series of 1,4-disubstituted 1,2,3-triazole analogues with structural modifications of the phenoxybenzylpiperidinyl and phenyl moieties. Evaluation in cell-based assays revealed potent and selective CCR8 agonistic activity of several derivatives. Molecular docking was applied to shed a light on their binding mode. Despite its suboptimal pharmacokinetic behaviour, a representative CCR8 agonist from this series, showed activity in a humanized model mimicking xenogeneic graft-versus-host disease.
Wang M, Ren J, Li Z
… +6 more, Shi H, Wang Q, Wang Y, Lu L, He Y, Dong H
Eur J Med Chem
· 2026 Jun · PMID 42302661
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Erycristagallin, a prenylated flavonoid natural product, has remained underexplored due to limited availability and incomplete mechanistic characterization. We herein report the first total synthesis of erycristagallin,...Erycristagallin, a prenylated flavonoid natural product, has remained underexplored due to limited availability and incomplete mechanistic characterization. We herein report the first total synthesis of erycristagallin, which was accomplished in 7 linear steps from commercially available starting materials and was readily performed on a gram scale. Mechanistic studies revealed a concentration-dependent membrane-targeting mode of action. At lower concentrations, erycristagallin caused membrane perturbation and functional impairment, whereas at higher concentrations, it caused extensive membrane damage. Erycristagallin also showed in vivo efficacy in a murine MRSA-infected skin wound model, and together these findings establish it as a promising anti-MRSA lead for further optimization and development.
Eur J Med Chem
· 2026 Jun · PMID 42302660
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Microbial secondary metabolites continue to be used as scaffolds for the development of medications for treatment of infectious and oncological diseases. Among them, aromatic polyketides occupy a prominent place due to t...Microbial secondary metabolites continue to be used as scaffolds for the development of medications for treatment of infectious and oncological diseases. Among them, aromatic polyketides occupy a prominent place due to their structural originality and broad biological activities. Heliomycin (also known as resistomycin), an antibiotic with pentacyclic benzo[cd]pyrenequinone core, produced by Streptomyces species, represents a structurally unique member of this class. Although historically heliomycin applied as a topical antibacterial or antiviral agent, it has attracted renewed interest owing to its versatile biological profile, including, antibacterial, antifungal, and particularly anticancer activities. This review provides a comprehensive and systematic analysis of heliomycin and its analogues, covering microbial production, biosynthetic pathways, structural elucidation, total synthesis and chemical modifications. Special attention is focused on semisynthetic derivatives of heliomycin aimed for improved solubility, stability, and pharmacological properties. The biological section summarizes current knowledge on molecular targets and mechanisms of action, including interactions with DNA, topoisomerases, epigenetic regulators (HDACs, SIRT1), tumor-associated enzymes (tNOX), oxidative stress pathways, and key signaling cascades. In vivo antitumor studies and emerging structure-activity relationships are also critically discussed. Taken together the available evidence positions heliomycin not as a single-target antibiotic, but as a pleiotropic bioactive scaffold with significant potential for further drug development.