Enterovirus 71 (EV71) is a major pathogen causing severe and fatal hand, foot, and mouth disease. Its strong neurotropism and rapid evolution pose an ongoing threat to infants and young children. To date, no specific ant...Enterovirus 71 (EV71) is a major pathogen causing severe and fatal hand, foot, and mouth disease. Its strong neurotropism and rapid evolution pose an ongoing threat to infants and young children. To date, no specific antiviral drug against EV71 has been approved, leaving a critical gap in clinical management. This review summarizes recent progress in the search for anti-EV71 drugs. The structural features of EV71 and key steps in its life cycle, including entry and replication, are first described. The evolution of drug discovery technologies is then traced, from traditional cytopathic effect-based screening to modern platforms such as computer-assisted virtual screening, reporter-carrying pseudovirus systems, and high-content imaging. Next, two main antiviral strategies are discussed: direct-acting agents that target the viral capsid, protease, and polymerase, and host-targeted approaches that modulate virus-dependent pathways including metabolism, signal transduction, and immune responses. In addition, the review highlights recent medicinal chemistry efforts in structure-based optimization of EV71 inhibitors, covering side-chain modifications, cyclization, prodrug design, and covalent binding engineering. By summarizing the mechanisms, optimization strategies, and current state of candidate drugs, this review aims to provide a practical reference for the development of antivirals against EV71 and other enteroviruses.
Drug resistance is a major barrier to effective hepatocellular carcinoma therapy, and autophagy targeting holds great potential for overcoming this issue. Using binding energy data from molecular docking with TBC1 domain...Drug resistance is a major barrier to effective hepatocellular carcinoma therapy, and autophagy targeting holds great potential for overcoming this issue. Using binding energy data from molecular docking with TBC1 domain family member 2 (TBC1D2) as the target, we rationally designed compound G2 featuring a piperazine moiety. Target binding was validated via a competitive immunofluorescence assay. The binding affinity of G2 was determined by surface plasmon resonance, yielding a dissociation constant (K) of 0.4 μM. Functional evaluation of G2 determined its aqueous solubility to be 0.3 mg/mL, with a half-maximal inhibitory concentration value of 80 ± 20 nM and a selectivity index of 23.1 in HCCLM3 cells. Subsequent mechanistic investigations revealed that this selectivity arose from the heightened responsiveness of TBC1D2 expression to G2 in HCCLM3 cells, thereby inducing selective autophagic cell death. In HCCLM3 xenograft mouse models, G2 showed excellent hepatic retention. G2 monotherapy (58.2% tumor growth inhibition) and its combination with sorafenib (70.9%) exerted superior antitumor activity versus sorafenib monotherapy (52.8%), with favorable safety. Collectively, our findings establish G2 as a promising therapeutic candidate for surmounting sorafenib resistance, characterized by selective antitumor activity against malignant hepatocellular carcinoma.
Wang T, Fu Y, Song B
… +5 more, Qin N, Zhang H, Tan D, Liu X, Cheng M
Eur J Med Chem
· 2026 Jun · PMID 42401084
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Recent studies have demonstrated that CYP1B1 plays a crucial role in tumor drug resistance. Paclitaxel, a first-line chemotherapeutic agent for solid tumors such as non-small cell lung cancer, often encounters limitation...Recent studies have demonstrated that CYP1B1 plays a crucial role in tumor drug resistance. Paclitaxel, a first-line chemotherapeutic agent for solid tumors such as non-small cell lung cancer, often encounters limitations in clinical efficacy due to drug resistance. Notably, CYP1B1 is significantly upregulated in paclitaxel-resistant cells, and its inhibition has been shown to effectively enhance the sensitivity of these resistant cells to paclitaxel. Our research group previously identified W-1, a key intermediate of Fexuprazan, as an inhibitor of CYP1B1 (IC = 0.16 μM). Building upon this lead compound, we designed and synthesized 52 target compounds through structural optimization. Systematic screening yielded multiple highly active and selective CYP1B1 inhibitors. Among these, the preferred compound C27 exhibited an IC value of 1.47 nM against CYP1B1 and demonstrated high selectivity over six major CYP isoforms. In the A549/Taxol drug-resistant cell model, C27 significantly enhanced the inhibitory effect of paclitaxel on the proliferation of resistant cells and effectively inhibited tumor cell migration and invasion. Pharmacokinetic studies revealed that C27 displayed good plasma stability and liver microsomal stability, with observable systemic exposure following both oral and intravenous administration in mice.
Cheng Z, Zou Z, Xin M
… +7 more, Wu S, Lu G, Du Z, Chen X, Chen G, Cai Y, Zou Y
Eur J Med Chem
· 2026 Jun · PMID 42398403
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BRD4 is a key epigenetic reader protein critically involved in the growth and proliferation of both hematological malignancies and solid tumors. Developing selective BRD4 BD1 inhibitors with novel scaffolds has emerged a...BRD4 is a key epigenetic reader protein critically involved in the growth and proliferation of both hematological malignancies and solid tumors. Developing selective BRD4 BD1 inhibitors with novel scaffolds has emerged as a promising strategy to address the limitations of current agents. Through a scaffold fusion approach, a series of 3-arylquinoxalin-2(1H)-one derivatives with promising BRD4 BD1 inhibitory activity were designed and synthesized. The optimized compound B12 demonstrated excellent BRD4 BD1 inhibitory activity (IC = 0.82 μM) and high selectivity over BRD4 BD2 (22-fold). B12 could effectively suppress the migration and proliferation of A549 cells (IC = 0.73 μM). Mechanistic studies revealed that B12 treatment could effectively downregulate c-myc and anti-apoptotic protein expression, increase DNA damage, elevate ROS levels, reduce mitochondrial membrane potential, and trigger apoptosis. Molecular docking suggested that B12 selectively binds to the active site of BRD4 BD1 through key hydrogen bonds with Asn140 and Asp144. Moreover, B12 showed favorable pharmacokinetic properties. Taken together, our research highlights that the 3-arylquinoxalin-2(1H)-one scaffold could serve as a valuable backbone for BRD4 inhibition and B12 is a promising candidate for further investigation.
Han G, Li C, Chen X
… +5 more, Su M, Yu R, Huang Z, Guo YW, Jin X
Eur J Med Chem
· 2026 Jun · PMID 42398402
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Through systematic optimization of lead D25, we identified two novel ROCK inhibitors, RX-021 and RX-044. Maintaining DFG interactions while optimizing linker flexibility was critical for potency. RX-044 showed excellent...Through systematic optimization of lead D25, we identified two novel ROCK inhibitors, RX-021 and RX-044. Maintaining DFG interactions while optimizing linker flexibility was critical for potency. RX-044 showed excellent ROCK1/2 inhibition (IC = 10.01 and 9.68 nM), favorable kinase selectivity, and no cytotoxicity in HTM cells. In a mouse ocular hypertension model, RX-021 achieved superior IOP reduction (5.38 ± 1.51 mmHg at 4 h) versus (S)-Netarsudil, with sustained 24 h efficacy and reversible HTM cell effects. Both compounds provided significant retinal neuroprotection, preserving retinal ganglion cell survival, restoring electroretinography responses, and ameliorating histopathological changes. Slit-lamp exams confirmed that initial ocular irritation subsided with extended dosing. These findings establish RX-021 and RX-044 as promising novel ROCK inhibitors with enhanced IOP-lowering efficacy and good retinal protective effects for glaucoma therapy.
Pulmonary fibrosis is a progressive and fatal disorder with high mortality, and current therapies offer modest efficacy. Single-target interventions are insufficient to address the complex pathological network involving...Pulmonary fibrosis is a progressive and fatal disorder with high mortality, and current therapies offer modest efficacy. Single-target interventions are insufficient to address the complex pathological network involving oxidative stress, inflammation, and cascaded fibrosis progression. Herein, a multi-stage cascade screening platform was established for integrating cytotoxicity, anti-inflammatory, antioxidant, and antifibrotic assessments. Systematic structure-activity relationship optimization led to the discovery of a novel benzoselenophene derivative, CX-Se13. It simultaneously regulates Keap1/Nrf2/HO-1/NQO1, NF-κB p65, TGF-β/Smads and YAP/TAZ-TEAD pathways, exerting integrated anti-inflammatory, antioxidant, and antifibrotic effects. In vitro and in vivo evaluations revealed that CX-Se13 suppresses the pathological progression of pulmonary fibrosis, reduces collagen deposition and pro-inflammatory cytokine levels, and exhibits potent protective effects in a bleomycin-induced mouse model of pulmonary fibrosis. CX-Se13 represents a novel, pleiotropic lead compound with high developmental potential, providing a new molecular entity and research paradigm for the development of antifibrotic therapies for pulmonary fibrosis.
Xin Z, Tan H, Xu Y
… +4 more, He P, Wang Z, Bu X, Wu H
Eur J Med Chem
· 2026 Jun · PMID 42398400
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Alzheimer's disease (AD) is the major cause of dementia and one of the most common chronic diseases affecting aging populations. As such, novel and effective therapeutic agents are urgently needed to address this growing...Alzheimer's disease (AD) is the major cause of dementia and one of the most common chronic diseases affecting aging populations. As such, novel and effective therapeutic agents are urgently needed to address this growing public health challenge. Given the involvement of glutaminyl cyclase (QC) and cannabinoid type 2 receptor (CB2R) dysregulation in AD progression, we designed, synthesized, and evaluated a series of biphenyl carboxamide derivatives as dual modulators targeting QC and CB2R. In vitro assays showed that most of the 35 compounds exhibited notable QC inhibitory and CB2R agonistic activity; for example, compound 18 demonstrated potent activity against both targets (QC, IC = 0.65 ± 0.07 μM; CB2R, EC = 0.32 ± 0.04 μM). Structure-activity relationship analysis indicated that the amide-linked motif (R) is critical for CB2R agonistic potency, while the introduction of a methoxy group (R) on the biphenyl scaffold enhances activity against both targets. Molecular docking further supported the interactions between these compounds and their respective protein targets. Taken together, these dual modulators targeting QC and CB2R warrant further investigation as potential therapeutic candidates for AD.
Zhang B, Li Z, Li D
… +12 more, Xiang Z, Huo G, Shi C, Duan L, Peng Y, Cao L, Cao S, Li L, Li Q, Huang J, Zhao D, Xia G
Eur J Med Chem
· 2026 Jun · PMID 42398399
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The retinoic acid receptor-related orphan receptor gamma t (RORγt) is a member of the nuclear receptor superfamily, expressed in lymphoid cells and driving Th17 cell differentiation and IL-17 production. The IL-17/IL-23...The retinoic acid receptor-related orphan receptor gamma t (RORγt) is a member of the nuclear receptor superfamily, expressed in lymphoid cells and driving Th17 cell differentiation and IL-17 production. The IL-17/IL-23 pathway is implicated in autoimmune and inflammatory diseases, such as inflammatory bowel disease (IBD). Targeting RORγt is considered a therapeutic intervention to suppress inflammation. Herein, we designed and synthesized a novel class of highly selective RORγt antagonists through scaffold-hopping and structure-activity relationship studies. Compound 14 (SPH7854) emerged as a preclinical candidate on the basis of its potent activity and favorable drug-like properties. SPH7854 demonstrated potent activity in preclinical models of inflammatory bowel disease and has advanced to clinical trials.
Liang J, Wu Y, Yang L
… +6 more, Xu B, Wang D, Shu HB, Dong C, Li S, Zhou HB
Eur J Med Chem
· 2026 Jun · PMID 42391931
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ESR1 mutation-driven endocrine therapy (ET) resistance remains a major challenge in breast cancer therapy. Herein, by integrating the advantages of PROTAC technology and coactivator-binding site (CBS) targeting strategy...ESR1 mutation-driven endocrine therapy (ET) resistance remains a major challenge in breast cancer therapy. Herein, by integrating the advantages of PROTAC technology and coactivator-binding site (CBS) targeting strategy in overcoming drug resistance, we developed a class of novel and potent ERα PROTAC degraders against ET-resistant breast cancer. Among them, compound NCP07 could potently degrade ERα and inhibited proliferation (IC = 0.13-1.22 μM) in both wild-type and ESR1-mutated cell lines. Mechanistic studies confirmed that compound NCP07 could not only specifically bind to CBS followed by inducing the formation of ERα-NCP07-VHL ternary complex, but also induce apoptosis and cell cycle arrest in drug-resistant cells. Besides, compound NCP07 also exhibited favorable metabolic stability and high safety properties. Totally, the potent anti-breast cancer activity and favorable metabolic stability of compound NCP07 not only indicated that PROTAC degrader targeting ERα CBS was an effective dual-action strategy for overcoming ESR1 mutation, but also was a promising candidate for further developing potent drugs against ET-resistant breast cancer.
Eur J Med Chem
· 2026 Jun · PMID 42391930
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The bromodomain and extra-terminal (BET) protein family are key epigenetic regulators. Their aberrant expression causes widespread gene dysregulation, which disrupts normal cellular functions and is strongly implicated i...The bromodomain and extra-terminal (BET) protein family are key epigenetic regulators. Their aberrant expression causes widespread gene dysregulation, which disrupts normal cellular functions and is strongly implicated in diverse human pathologies, including inflammation, cancer, cardiovascular diseases, and central nervous system disorders. Currently, several BET inhibitors have entered clinical trials. However, most are pan-BET inhibitors, whose lack of selectivity is associated with adverse effects such as dose-limiting toxicities and thrombocytopenia. Therefore, the development of highly selective inhibitors targeting individual bromodomains (BD1 or BD2) within the BET family has become a key focus in the field. This review outlines the structure and function of BET proteins and summarizes recent advances in the discovery of domain-selective BET inhibitors. It aims to deepen the mechanistic understanding of BET proteins and lay the groundwork for the rational design of next-generation, high-selectivity therapeutics.
Wang Y, Sang J, Li H
… +15 more, Ren X, Chen C, Zheng N, Xiao H, Wei Y, Xu L, Jiang R, Zhang W, Xu Z, Ge L, Zhu J, Xiong B, Chen Y, Feng F, Sun H
Eur J Med Chem
· 2026 Jun · PMID 42391929
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Targeting multiple pathological mechanisms holds significant potential for Alzheimer's disease (AD) therapy. Here, we designed 50 hybrids combining the benzimidazole-aminofurazan scaffold of a BChE inhibitor (S06-1064) w...Targeting multiple pathological mechanisms holds significant potential for Alzheimer's disease (AD) therapy. Here, we designed 50 hybrids combining the benzimidazole-aminofurazan scaffold of a BChE inhibitor (S06-1064) with the 1,2,4-oxadiazole moiety of an Nrf2 activator (6). After four optimization rounds, S27-1046 and S27-1047 emerged as potent, selective BChE inhibitors and Nrf2 activators (S27-1046: eqBChE IC = 2.51 ± 1.51 nM, hBChE IC = 128.30 ± 16.89 nM, FP IC = 188.20 ± 57.11 nM, 4.73-fold ARE induced fold at 20 μM; S27-1047: eqBChE IC = 7.16 ± 2.96 nM, hBChE IC = 296.10 ± 55.78 nM, FP IC = 36.87 ± 23.07 nM, 7.42-fold ARE induced fold at 20 μM). They directly bind Keap1, disrupt Keap1-Nrf2 interaction, enhance antioxidant enzyme expression, and activate the GSH-GPX4 axis to inhibit Aβ-induced ferroptosis. Both compounds also protect against oxidative stress and neuroinflammation. S27-1047 showed superior Nrf2 activation and Keap1 binding, thus was selected for in vivo evaluation. In an Aβ-induced AD mouse model, S27-1047 significantly improved cognition, outperforming mono- or combination therapies. It has 12.62% oral bioavailability and crosses the BBB. This work presents multi-target agents targeting BChE, Nrf2, and ferroptosis for effective AD therapy.
Eur J Med Chem
· 2026 Jun · PMID 42385348
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Targeted protein degradation (TPD) has emerged as an important therapeutic strategy for addressing challenging protein targets. While Proteolysis-Targeting Chimeras (PROTACs) are the leading TPD approach, their reliance...Targeted protein degradation (TPD) has emerged as an important therapeutic strategy for addressing challenging protein targets. While Proteolysis-Targeting Chimeras (PROTACs) are the leading TPD approach, their reliance on a limited set of E3 ligases poses challenges, including tissue-specific restrictions and the emergence of drug resistance. To address these limitations, we previously developed the HEMTAC (HEat shock protein-Mediated TArgeting Chimeras) platform, which recruits HSP90 to induce target protein degradation. Building on this concept, the current study expands the HEMTAC framework by integrating HSP70, a key molecular chaperone, to target the androgen receptor (AR). We designed and synthesized a series of novel HSP70-recruiting HEMTACs by linking an HSP70 ligand (a derivative of VER-155008) with an AR-binding ligand. Biological evaluation identified compound 39 as an active degrader that induced substantial AR degradation in LNCaP prostate cancer cells. This work supports the feasibility of recruiting HSP70 for TPD and provides a molecular tool for AR-degradation research, thereby expanding the TPD toolbox for future drug discovery.
Sun XL, Zhang LX, Zhang J
… +11 more, Zhang T, Wang CF, Fan SR, Ding X, Xiang ZR, Yu ZZ, Wang YT, Xiong SD, Chen DZ, Zheng YT, Hao XJ
Eur J Med Chem
· 2026 Jun · PMID 42385347
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During the COVID-19 pandemic, the substantial global health burden imposed by SARS-CoV-2 and its variants-driven by high transmissibility, virulence, and frequent mutations-has highlighted the urgent need for broad-spect...During the COVID-19 pandemic, the substantial global health burden imposed by SARS-CoV-2 and its variants-driven by high transmissibility, virulence, and frequent mutations-has highlighted the urgent need for broad-spectrum antiviral agents as a key component of pandemic preparedness. In our preliminary screening, vilazodone was identified as an inhibitor of SARS-CoV-2 replication via targeting the METTL3 protein. Building on this finding, a total of 33 vilazodone derivatives were designed and synthesized in the present study to enhance antiviral potency and improve the selectivity index. Among these derivatives, compound D4 exhibited the most potent anti-SARS-CoV-2 activity, surpassing that of the positive control remdesivir. Its potent antiviral efficacy and favorable therapeutic index provide an important basis for antiviral drug development. However, its moderate binding to METTL3 and weak inhibitory activity suggest that its antiviral activity may be mediated through targets other than METTL3. Although this finding poses a challenge to the METTL3-targeting strategy, it also opens up new research directions for further dissecting the mechanism of action of this compound and exploring its potential targets.
Huang SQ, Chen XZ, Chen LY
… +7 more, Wang HL, Yang AT, Yao Y, Ying XY, Luo X, Yin XG, Zhu KW
Eur J Med Chem
· 2026 Jun · PMID 42378849
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Arecoline and arecaidine, the primary alkaloids in betel nut, are responsible for betel-quid chewing addiction. Vaccination against small molecules is a promising approach but limited by their weak immunogenicity. Invari...Arecoline and arecaidine, the primary alkaloids in betel nut, are responsible for betel-quid chewing addiction. Vaccination against small molecules is a promising approach but limited by their weak immunogenicity. Invariant NKT cells (iNKT cells) serve as a key bridge between innate and adaptive immunity, providing cognate B cell help and enhancing antibody responses. Herein, we developed two fully synthetic, structurally defined arecoline (Arec) and arecaidine (Areca) vaccine candidates with NKT cell agonist α-Galactosylceramide (αGalCer) as a built-in adjuvant. Both these vaccine candidates efficiently promoted class switching from IgM to IgG, with a response dominated by the IgG1 and IgG3 subclasses. Cross-reactivity analysis found that antibodies elicited by Arec-αGalCer recognized both arecoline and guvacoline but with reduced affinity for the latter. Meanwhile, antibodies induced by Areca-αGalCer specifically recognized arecaidine, and the affinity was comparable to that of Arec-αGalCer antibodies for arecoline. In vivo, Arec-αGalCer vaccination caused a modest mitigation of arecoline-induced hypothermia. In addition, a mixed vaccine formulation elicited a broader serological response than the single vaccine.
Shah SJA, Hayat M, Inam M
… +2 more, Ahmed B, Subthain H
Eur J Med Chem
· 2026 Jun · PMID 42372394
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GPR120 (free fatty acid receptor 4, FFAR4) has recently emerged as promising therapeutic target with implications for therapies targeted at neurodegeneration, metabolic disorders, cancer, inflammation and cardiovascular...GPR120 (free fatty acid receptor 4, FFAR4) has recently emerged as promising therapeutic target with implications for therapies targeted at neurodegeneration, metabolic disorders, cancer, inflammation and cardiovascular diseases. The context dependent signaling and the tissue-specific expression of GPR120 has further complicated the drug development efforts. In this review, we comprehensively examined the current landscape of GPR120 modulation, integrating the GPR120 pharmacology with recent advances in the orthosteric and allosteric modulation, structure-based drug design and computational discovery strategies specifically targeted towards GPR120 receptors and downstream signaling. This review focuses on the functional significance of GPR120 isoforms, their site-specific expression and signal-bias and their role across obesity, type 2 diabetes, neurodegeneration, cancer, inflammation and cardiovascular pathologies. Orthosteric agonists, antagonists and allosteric modulators including endogenous, synthetic and computational derived modulators are systematically analyzed. Structure-based design strategies enabling optimization of the modulators, revealing critical mechanisms of binding, activation, sensitization and downstream signaling has been extensively covered, revealing the critical aromatic residue network (W198, W207, F115, F211, F303/F304) and indispensable role of R99 polar head groups recognition and interactions, conserved activation toggle switch W277, triad amino acids P5.50-I3.40-F6.44 triad, and ionic lock disruption (R136-D259) as a activation hallmarks. Inactive-active state stabilization via W277-N313 constraints informed antagonist development. Emerging allosteric modulation of GPR120 through natural partial agonists are comprehensively discussed. Finally, in this review we summarized comprehensively the computational methodologies spanning around homology modelling in pre- and post-cryo-EM era to native structure-guided approaches, multi-software docking, molecular dynamics simulations and virtual screening pipeline - including a large scale hexapeptide library screening yielding stereo-specific amino acid peptides with >100-fold potency. This review provides a roadmap for rational design of GPR120-targeted therapeutics that are pathway-selective and tissue-specific.
Soogary G, Maine R, Smith GS
… +1 more, Hurdayal R
Eur J Med Chem
· 2026 Jun · PMID 42372393
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Cutaneous leishmaniasis, the most prevalent form of the parasitic and vector-borne disease of leishmaniasis, is mainly caused by Leishmania major (L. major) in the developing world. With no vaccine available for primary...Cutaneous leishmaniasis, the most prevalent form of the parasitic and vector-borne disease of leishmaniasis, is mainly caused by Leishmania major (L. major) in the developing world. With no vaccine available for primary prophylaxis, secondary prophylaxis comprises commercially available therapeutic drugs, such as amphotericin B and miltefosine. However, these agents are associated with parasite-specific drug resistance, severe drug-induced toxicity to the host and high treatment costs. In this study, the strategies of molecular hybridisation of pharmacologically relevant scaffolds and metal incorporation were combined to synthesise a set of novel hybrid compounds containing the quinoline, benzimidazole, ferrocene and triazole scaffolds. The hybrids showed adequate stability at 37 °C over a 48-h incubation period and antileishmanial studies on L. major promastigotes revealed one lead compound (4a) with potent activity (IC of 6.63 ± 0.66 μM), comparable with the standard clinical drug amphotericin B (IC of 4.96 ± 0.13 μM). In addition, compound 4a showed significant efficacy (IC of 15.4 ± 0.5 μM) against L. major amastigotes in murine bone marrow-derived macrophages (BMDMs), albeit less potent than amphotericin B (IC of 5.47 ± 0.43 μM). The lead compound was also minimally toxic against murine BMDMs which resulted in a strong selectivity index. Mechanistic profiling in L. major promastigotes further revealed that compound 4a induced a concentration-dependent increase in intracellular reactive oxygen species, mitochondrial membrane depolarisation, and progressive parasitic plasma membrane impairment. Taken together, the hybrid architecture of these compounds may provide opportunities for further derivatisation, optimisation, and structure-activity relationship (SAR) studies to improve potency and selectivity through potential multimodal mechanisms of action, thus representing a nascent roadmap towards novel antileishmanial agents.
Eur J Med Chem
· 2026 Jun · PMID 42372392
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The 2-pyridone scaffold constitutes a privileged and versatile heterocyclic framework in medicinal chemistry. Existing reviews have largely concentrated on synthetic methodologies, and a comprehensive overview of this sc...The 2-pyridone scaffold constitutes a privileged and versatile heterocyclic framework in medicinal chemistry. Existing reviews have largely concentrated on synthetic methodologies, and a comprehensive overview of this scaffold in medicinal chemistry remains lacking. This review systematically surveys the applications of 2-pyridone-based compounds from 2010 to 2026, with an emphasis on design strategies, structure-activity relationships (SAR), druggability optimization, and biological activities. The applications of these derivatives span diverse disease categories, including cancer, infectious diseases, central nervous system (CNS) disorders, as well as immunological, metabolic, and cardiovascular conditions. Notably, the scaffold has demonstrated distinct value in the development of highly selective kinase inhibitors. In summary, the 2-pyridone scaffold continues to provide a robust and adaptable platform for the discovery of next-generation therapeutics, and this review aims to serve as a comprehensive reference for rational drug design while inspiring novel insights into the development of 2-pyridone-based drug candidates.
Eur J Med Chem
· 2026 Jun · PMID 42364460
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The targeted delivery of metal complexes to specific cell populations based on metabolic characteristics represents a significant and complex challenge, with broad potential applications in the therapy of diseases such a...The targeted delivery of metal complexes to specific cell populations based on metabolic characteristics represents a significant and complex challenge, with broad potential applications in the therapy of diseases such as cancer. This review systematically summarizes the recent advancements in the application of glycoconjugated metal complexes for targeted cancer therapy. Capitalizing on the Warburg effect-a hallmark of cancer metabolism characterized by heightened glucose uptake-these complexes are designed to selectively target cancer cells that overexpress glucose transporters. By conjugating bioactive metal centers (e.g., Pt, Ru, Au, Ir) with sugar moieties, these complexes significantly enhance tumor selectivity, improve aqueous solubility, and reduce systemic toxicity compared to conventional chemotherapeutics. This article comprehensively reviews their application across a wide range of cancers, including lung, breast, colorectal, ovarian, cervical, skin, etc., highlighting their mechanisms of action, superior efficacy, and improved safety profiles in both in vitro and in vivo models. The rational design strategies, structural-activity relationships, and emerging combination therapies are also discussed. Glycoconjugated metal complexes represent a promising frontier in the development of targeted, biocompatible anticancer agents with the potential to overcome the limitations of traditional metal-based drugs.
Eur J Med Chem
· 2026 Jun · PMID 42364459
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For the development of low molecular weight oral drugs, optimizing absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic (PK) properties are crucial. Historically, optimization strategies often e...For the development of low molecular weight oral drugs, optimizing absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic (PK) properties are crucial. Historically, optimization strategies often emphasized individual ADME properties over integrated PK optimization. Such individual parameter optimization approaches in rank ordering compounds focus on parameters other than PK and dose drivers. Emphasizing individual thresholds and indices may result in discarding compounds that do not meet these specific criteria but could have a balanced profile suitable as a drug. Integrated approaches pivoted on dose tend to utilize a one-compartmental model intended to guide a balanced parameter optimization towards a desired product profile. By employing various visualizations of PK parameter combinations alongside project-specific thresholds, the concept outlines how property combinations influence early dose estimation and related PK parameters, supporting the identification of clinical candidates. The primary objective herein is to provide a framework for integrating basic ADME/PK principles with model predictions and custom visualizations for systematic PK and dose optimization, whereby enabling ideation prior to synthesis and subsequently integrating experimental results during lead optimization.