Eur J Med Chem
· 2026 Oct · PMID 42166815
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This study reports the rational design, synthesis, and preliminary evaluation of a novel series of quinazolin-4-one derivatives. These compounds were developed as potential dual inhibitors of EGFR and c-SRC kinases to ex...This study reports the rational design, synthesis, and preliminary evaluation of a novel series of quinazolin-4-one derivatives. These compounds were developed as potential dual inhibitors of EGFR and c-SRC kinases to explore their utility in addressing bypass-related signaling in cancer cells. Through systematic optimization, compound 9b emerged as a lead candidate, demonstrating potent and balanced enzymatic inhibition with IC values of 0.057 μM (EGFR) and 0.073 μM (c-SRC). To our knowledge, this represents an unprecedented achievement in the development of dual EGFR/c-SRC inhibitors with this potency profile. In cellular assays, 9b exhibited significant antiproliferative activity, induced G0/G1 cell cycle arrest, and triggered apoptosis via modulation of p53, Bax, and Bcl-2 expression. Molecular docking and dynamics simulations confirmed stable binding modes within both kinase active site key amino acids, forming critical hinge-region interactions. Computational ADMET predictions further support its favorable drug-like properties. Collectively, 9b represents a promising dual-targeted therapeutic lead worthy of advanced preclinical development.
Song J, Lim S, Jeon E
… +4 more, Kim C, Park SM, Park JB, Sim T
Eur J Med Chem
· 2026 Oct · PMID 42161102
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Mutations and rearrangements of Rearranged during Transfection kinase (RET) are highly implicated with thyroid cancer. This study aimed to explore the therapeutic potential of a targeted protein degradation (TPD) strateg...Mutations and rearrangements of Rearranged during Transfection kinase (RET) are highly implicated with thyroid cancer. This study aimed to explore the therapeutic potential of a targeted protein degradation (TPD) strategy against RET-associated medullary thyroid carcinoma (MTC). The investigation of the structure-activity relationship (SAR) led to the identification of a novel RET-CRBN degrader, JW15 which possesses excellent degradation capability (DC = 0.3 nM) and potent anti-proliferative activity (GI = 1.2 nM) on TT cells (MTC). Mechanistic studies revealed that JW15 degrades RET kinase via the ubiquitin-proteasome system (UPS) and effectively recruits cereblon (CRBN) E3 ligase in target engagement assays. Notably, JW15 exhibited superior suppression of RET phosphorylation and downstream signaling compared with selpercatinib. In addition, JW15 demonstrated greater efficacy than selpercatinib in inducing apoptosis and suppressing colony-forming capacity on TT cells, particularly at a concentration of 1 nM. JW15 administered intravenously at 20 mg/kg twice weekly demonstrated significant antitumor efficacy, showing 70% tumor growth inhibition in RET Ba/F3 xenograft models over 13 days. Taken together, our study provides fundamental guidelines for structure-guided design and optimization for the development of RET degraders, offering a promising strategy for targeting RET-driven cancers.
Mandal B, Halder S, Brandao P
… +4 more, Bera S, Bera P, Jana K, Bera P
Eur J Med Chem
· 2026 Oct · PMID 42161101
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We designed and synthesized a series of coordination environments with variation in bioinorganic element, spatial configuration, molecular size, charge distribution, and flexibility to evaluate their influence on oncogen...We designed and synthesized a series of coordination environments with variation in bioinorganic element, spatial configuration, molecular size, charge distribution, and flexibility to evaluate their influence on oncogenic bioprocess through modulation of molecular interaction and bioactivity. A hybrid molecule of thiazole-benzothiazole core (TbtH) with NS donor sites has been reacted with metal (Zn, Ni, and Cd) salts to produce both neutral (inner metallic) and ionic complexes. The ligand (TbtH) has a planar structure and forms distorted octahedral complexes (C1-C5) as ascertained by X-ray crystallography. Electron delocalisation in different frontier molecular orbitals (FMOs) reveals the electronic transition sequence as C2, C4 > C5 > C1 > C3. The order suggests the innermetallic C2 and C4 are soft metal complexes and especially demonstrate superior biological activity. The compounds demonstrated potent cytotoxicity in a dose-dependent manner, indicating a favorable and selective antitumor activity against various human cancer cells, viz., breast cancer (MDA-MB-231 and MCF-7), lung cancer (A549), and liver cancer (HepG2). Among the compounds, C2 demonstrates robust and selective cytotoxicity across cancer cell models and has emerged as the lead cytotoxic agent against triple-negative breast cancer cells with the IC value of 9.46 ± 0.48 μM. The concurrence of mitochondrial depolarisation and caspase-3 activation elucidates a programmed cell death mechanistic cascade inducing intrinsic apoptosis in MDA-MB-231 cells through mitochondrial dysfunction and downstream caspase engagement. Besides the C2 also inhibits Topoisomerase II activity in a dose-dependent manner as envisaged by the kDNA decatenation assay. Molecular docking and molecular dynamics studies corroborated the experimental findings, identifying C2 as the most suitable candidate for MDA-MB-231 cells with the highest binding free energy (-7.41 kcal/mol). RMSD and RMSF analyses also confirm that both the protein and substrate remain stable within the binding pocket, with minimal structural fluctuations. Overall, C2 demonstrates superior stability, binding affinity, and cytotoxic potential, making it the most promising candidate among the reported compounds.
Hao Y, Wang R, Liao H
… +7 more, Wang M, Ye Z, Liu Y, Lv Q, Zhang D, Yan L, Xie F
Eur J Med Chem
· 2026 Oct · PMID 42161100
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Invasive candidiasis, particularly those caused by drug-resistant Candida albicans, poses a serious threat worldwide. To develop novel antifungal agents, a series of triazine thiosemicarbazide derivatives were designed a...Invasive candidiasis, particularly those caused by drug-resistant Candida albicans, poses a serious threat worldwide. To develop novel antifungal agents, a series of triazine thiosemicarbazide derivatives were designed and synthesized via structure optimization. Structure-activity relationship analysis revealed that the thiosemicarbazide moiety is essential for synergistic antifungal activity. Notably, compound A21 exhibited excellent synergistic effects with fluconazole (FCZ) against resistant C. albicans (lowest FICI range: 0.002-0.005), restoring the efficacy of other azoles and showing monotherapy activity against Candida glabrata (MIC = 1 μg/mL) and Cryptococcus neoformans (MIC = 4 μg/mL). Mechanistically, A21 reversed FCZ resistance by downregulating ERG genes, as well as drug resistance- and virulence-related genes, when combined with FCZ. With enhanced metabolic stability in human liver microsomes (HLM) and mouse liver microsomes (MLM) and a favorable safety profile, A21 in combination with FCZ displayed potent in vivo efficacy against Galleria mellonella and mice infected with resistant C. albicans. Therefore, A21 represents a promising lead for combating resistant candidiasis.
Pérez-Rodríguez D, Amesty Á, Oramas-Royo S
… +5 more, Fernández-Vega E, Cuadrado I, Hortelano S, de Las Heras B, Estévez-Braun A
Eur J Med Chem
· 2026 Oct · PMID 42155172
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Targeting the NLRP3 inflammasome has become an attractive therapeutic strategy for a wide range of inflammatory and immune-mediated diseases due to its central role in innate immunity and pathological inflammation. In th...Targeting the NLRP3 inflammasome has become an attractive therapeutic strategy for a wide range of inflammatory and immune-mediated diseases due to its central role in innate immunity and pathological inflammation. In this study, a series of novel grandiflorenic acid derivatives were rationally designed and semisynthesized as effective covalent NLRP3 inhibitors. These compounds inhibited IL-1β release in the nanomolar range, with compound 5 identified as the most potent derivative of the series (IC = 1.36 ± 0.21 nM). Several selected derivatives (4, 5, 8, 17, 20 and 21) markedly reduced IL-1β release following activation by diverse stimuli, including nigericin, ATP, imiquimod, or MSU crystals, demonstrating a strong and stimulus-independent inhibition of NLRP3 signaling. Additionally, representative compounds 5, 8, and 17 significantly decreased LDH release, indicating effective suppression of inflammasome-mediated pyroptosis. Molecular dynamic simulations confirmed the stable binding of compound 5 within the ATP-binding site of NLRP3. In silico ADME analysis further predicted good human oral absorption for compounds 4, 5, 8, 17, 20 and 21.
Czuba M, Szafrańska K, Kolaczkowski M
… +1 more, Marcinkowska M
Eur J Med Chem
· 2026 Oct · PMID 42155171
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TRPML1, a lysosomal Ca channel, has emerged as a clinically relevant target due to its genetic and mechanistic links to lysosomal storage disorders and neurodegenerative diseases, including Gaucher disease, Parkinson's d...TRPML1, a lysosomal Ca channel, has emerged as a clinically relevant target due to its genetic and mechanistic links to lysosomal storage disorders and neurodegenerative diseases, including Gaucher disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. This evidence has prompted TRPML1 drug discovery efforts across academia and industry, with several small-molecule agonists advancing toward clinical development. In this review, we provide a comprehensive overview of the therapeutic potential of TRPML1 as a molecular target from a medicinal chemistry perspective. We summarize the structural basis of channel activation and inhibition, highlighting insights from recent cryo-EM studies that define the principal ligand-binding sites and mechanisms of allosteric modulation. We systematically survey the chemical space of TRPML1 ligands reported to date, including diverse agonist and antagonist chemotypes, and extend this analysis to encompass undisclosed or recently disclosed compounds emerging from industry pipelines. Furthermore, we discuss key determinants of ligand design and developability, including the challenges associated with targeting a deeply embedded, lipophilic binding pocket within the membrane. Overall, the available evidence positions TRPML1 as a promising target for small-molecule drug discovery and provides a framework for the rational design of next-generation lysosome-directed therapeutics.
Duan S, Hu S, Fang Y
… +13 more, Liu M, Lin Y, Gui J, Tang S, Zhang C, Zhang D, Mai X, Yao S, Liu J, Shao L, Fu W, Wang Y, Li W
Eur J Med Chem
· 2026 Oct · PMID 42155170
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Kappa opioid receptor (KOR) agonists remain promising candidates for the development of antinociceptive and antipruritic therapeutics. Here, we report the design, synthesis, and biological evaluation of a series of N-cyc...Kappa opioid receptor (KOR) agonists remain promising candidates for the development of antinociceptive and antipruritic therapeutics. Here, we report the design, synthesis, and biological evaluation of a series of N-cyclopropylmethyl-7α-piperazinyl-6,14-endoethano-tetrahydronorthebaines derived from the 4,5-epoxymorphinan scaffold. Several derivatives displayed subnanomolar to low-nanomolar KOR affinity together with pronounced subtype selectivity in radioligand binding assays. Among them, compound 10e exhibited exceptionally high KOR affinity (K = 1.6 pM) and more than 100-fold selectivity over μ- and δ-opioid receptors. In cAMP-based functional assays, compounds 7, 8b, and 10e behaved as KOR agonists, with compound 10e displaying the highest potency (EC = 1.41 nM). However, in Tango assays, compound 10e displayed a higher EC value of 4912 nM, suggesting G-protein biased signaling. In vivo,10e produced dose-dependent antinociceptive activity in the acetic-acid writhing assay and robust antipruritic effects, while showing no effect in the hot-plate test at doses up to 40 mg/kg. These findings demonstrate that incorporating a 7α-piperazinyl substituent into the 4,5-epoxymorphinan framework yields a highly potent and KOR-selective agonist, and highlight the critical role of the terminal phenylacetamido group in modulating receptor affinity and subtype selectivity.
Zhao Y, Wang Y, Cui Y
… +5 more, Xu F, Wang W, Hou W, Li Y, Wei H
Eur J Med Chem
· 2026 Oct · PMID 42155169
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Neurotensin Receptor 1 (NTSR1) is a Class A G protein-coupled receptor(GPCRs) that exhibits high affinity for neurotensin. Overexpression of NTSR1 in various cancers makes it a promising target for tumor-specific imaging...Neurotensin Receptor 1 (NTSR1) is a Class A G protein-coupled receptor(GPCRs) that exhibits high affinity for neurotensin. Overexpression of NTSR1 in various cancers makes it a promising target for tumor-specific imaging and therapy. Currently, radioligands such as the small-molecule antagonist 3BP-227 and the peptide agonist [Ga]DOTA-NT-20.3 have entered clinical trials. However, NTSR1-targeted radiopharmaceuticals still face challenges including suboptimal tumor-to-background ratios, high renal accumulation, and the lack of validated theranostic pairs for patient stratification. Studies have shown that pharmacokinetic modifiers such as hydrophilic linkers and albumin-binding moieties can significantly modulate ligand bioavailability as well as imaging and therapeutic efficacy. This review systematically elaborates recent advances in the development of compounds targeting NTSR1, focusing on the molecular structures and biological activities of radiolabeled peptide and non-peptide derivatives. It emphasizes their applications in tumor imaging diagnosis and targeted radiotherapy. The article aims to provide a reference for drug development based on NTSR1 ligands.
Xu Y, Wang Z, Yang T
… +5 more, Wang H, Hou L, Wang X, Yang G, Luo Y
Eur J Med Chem
· 2026 Oct · PMID 42155168
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The overactivated CDK6/Cyclin D3 complex is considered to be associated with poor prognosis in patients with NSCLC, thus developing CDK6/Cyclin D3 inhibitors is expected to provide new options for NSCLC patients. This st...The overactivated CDK6/Cyclin D3 complex is considered to be associated with poor prognosis in patients with NSCLC, thus developing CDK6/Cyclin D3 inhibitors is expected to provide new options for NSCLC patients. This study successfully utilized a mixed virtual screening workflow based on artificial intelligence, pharmacophores, and docking to rapidly identify multiple CDK6/Cyclin D3 inhibitors from a compound library consisting of 12,563 compounds, achieving a hit rate of over 40% (2 out of 5 selected candidate compounds). Among these, compound 2 exhibited the most potent CDK6/Cyclin D3 inhibitory activity, with an IC value of 38.6 nM, comparable to CDK6 inhibitors in clinical trial phases. In vitro antitumor activity indicated that compound 2 has strong proliferation-inhibitory activity against NSCLC, with IC values below 78 nM for two NSCLC cell lines, showing promise for further exploration. Kinetic simulation results revealed that compound 2 binds to the ATP-binding pocket of CDK6, stabilizing its conformation through hydrogen bond interaction with Val101 and ionic interaction with Asp104, providing new insights for the development of subsequent CDK6 inhibitors.
Eur J Med Chem
· 2026 Oct · PMID 42150247
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Alzheimer's disease (AD) is a degenerative neurological disorder characterized by a deterioration in cognitive abilities, especially memory and learning. The main aim of this study is to evaluate the effects of our agent...Alzheimer's disease (AD) is a degenerative neurological disorder characterized by a deterioration in cognitive abilities, especially memory and learning. The main aim of this study is to evaluate the effects of our agents on oxidative stress, neuroinflammation, cognitive function, and behavioral performance in an LPS-induced AD animal model and comprehensive in vitro and in vivo assays. The synthesized compounds, namely 4b, 5b, 6, 8a-d, and 11a-c, revealed acetylcholinesterase inhibitory activity (3.50-5.91 nM) superior to that of the reference drug donepezil (6.33 nM). The IC value of 11a the most active candidate was 3.50 nM against hAChE, with a significant reduction in amyloid-β accumulation by 70% compared to LPS-treated groups, it also reduced neuronal damage, as evidenced by histopathological analysis. Compared to LPS treated groups, 11a decreased brain GFAP, NLRP3, NF-κB, APOE and MDA by 76%, 65%, 48%, 75%, and 59% respectively while increasing GSH by 81%. Molecular docking simulation, along with 100 ns molecular dynamics (MD) simulations conducted on the AChE-ligand complexes, demonstrated favorable conformations of ligand-protein complex throughout the simulations, predicting a dual binding to the CAS and PAS regions of the enzyme which is consistent with kinetic studies against hAChE. Moreover, the chemical stability and reactivity of the drug-target complex were evaluated using global and local reactive descriptors. These findings suggested that compound 11a possessed promising potential as a multi-target lead compound for the development of anti-Alzheimer treatments based on cholinergic, amyloidogenic, and neuroinflammation, through GFAP/NF-κB/APOE/NLRP3 signaling axis.
Zhang LL, Niu B, Chen DH
… +13 more, Wang B, Zeng YY, Wu YZ, Feng HW, Zhou QH, Zhao TL, Pei JJ, Zuo R, Yu FD, Ji XJ, Wu J, Ma CY, Xu D
Eur J Med Chem
· 2026 Oct · PMID 42150246
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The receptor tyrosine kinase AXL has emerged as a promising target for overcoming therapeutic resistance in both solid and haematological tumors. Currently, multiple strategies have been established to block AXL activity...The receptor tyrosine kinase AXL has emerged as a promising target for overcoming therapeutic resistance in both solid and haematological tumors. Currently, multiple strategies have been established to block AXL activity in tumor cells. Among these, Small-molecule inhibitors exert a more potent inhibitory effect. Although a number of small-molecule compounds have been reported, their ADME profiles and inhibitory efficacy still have considerable potential for further optimization. In this paper, we describe a series of 2,4,5-substituted pyrimidine AXL kinase inhibitors featuring a phosphine oxide moieties that exhibit more powerful inhibitory effect and an improved in vivo pharmacokinetic profiles. Several challenges such as high clearance, hERG risk, CYP450 inhibition, and poor oral pharmacokinetics (PK) were addressed, leading to the identification of NTQ2494 (5p) as the optimal compound. NTQ2494 (5p) exhibited favorable ADMET properties and demonstrated significantly enhanced in vivo efficacy in an MV-4-11 xenograft model compared to TP-0903. NTQ2494 is currently under Phase I clinical evaluation for the treatment of advanced hematological malignancies and solid tumors.
Yeasrim S, Ahmad HT, Chen M
… +4 more, Li X, Gao Z, Sun H, Xing S
Eur J Med Chem
· 2026 Oct · PMID 42150245
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Numerous illnesses, including cancer, inflammation, and metabolic disorders, have been linked to the enzyme aldo-keto reductase family 1 member B10 (AKR1B10). The pathogenic consequences of AKR1B10, its structural and fu...Numerous illnesses, including cancer, inflammation, and metabolic disorders, have been linked to the enzyme aldo-keto reductase family 1 member B10 (AKR1B10). The pathogenic consequences of AKR1B10, its structural and functional characteristics, and the rationale behind concentrating on it during drug discovery are examined in this review. The classification, structure-activity relationships, and computational design of AKR1B10 inhibitors are discussed, along with the current status of their studies. The challenges of developing inhibitors, such as selectivity, resistance mechanisms, and pharmacokinetics, are also analyzed. Finally, we examine prospective insights and advancements for the future, including combination treatments, novel chemical scaffolds, and the expansion of therapeutic applications outside cancer.
Eur J Med Chem
· 2026 Oct · PMID 42143942
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Cholesteryl ester transfer protein has been a long-sought target for the treatment of dyslipidemia because of its prime function in the remolding of lipoprotein particles and the reverse transport of cholesterol. During...Cholesteryl ester transfer protein has been a long-sought target for the treatment of dyslipidemia because of its prime function in the remolding of lipoprotein particles and the reverse transport of cholesterol. During the past couple of decades, a huge variety of CETP inhibitors has been generated from intensive biomedical research, taking on diverse primary scaffolds from discovery to late-stage development. Despite their promising beginnings, the first-generation CETP inhibitors have been realized to possess a couple of obvious flaws, such as the existence of off-target toxicities, high lipophilicity, sub-optimized pharmacokinetic properties, and inconsistent results in the outcomes of clinical studies, leading to the termination of a couple of candidates in late-stage development. Therefore, the need for the next-generation approach that considered optimizations in the pharmacokinetics and physiological-chemical properties and the reduction of ligand efficiency and primary scaffolds allowed for the development of pharmacokinetic and late-stage CETP inhibitors with enhanced properties. Here, a thorough discussion to analyze the leveraging of biomedical principles to further develop late-generation CETP inhibitors with major improvements from the pharmacokinetics and results of the primary clinical studies characterizing a huge variety of the first-generation CETP inhibitors with diverse primary bioactive scaffolds will be undertaken.
Tang J, Ma X, Wang X
… +11 more, Xia G, Zhang X, Yu Z, Zhu J, Li X, Wu Z, Meng R, Ni Y, Fan T, Li Y, Song D
Eur J Med Chem
· 2026 Oct · PMID 42143941
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An ester group can serve as a covalent warhead to acylate amino acid residues around the active cavity of the target protein, thereby silencing its biological function. In this study, taking 8-(benzoyloxy) cycloberberine...An ester group can serve as a covalent warhead to acylate amino acid residues around the active cavity of the target protein, thereby silencing its biological function. In this study, taking 8-(benzoyloxy) cycloberberine (1) as the lead, twenty-seven 8-esterified cycloberberine (CBBR) derivatives were continuously synthesized and evaluated for their anti-tumor activities. Among them, compound 8a exhibited an appealing potency against a variety of tumor cells with IC values ranging 1.91-5.09 μM, significantly outperforming the lead 1. Cell cycle analysis showed 8a-induced G2/M phase arrest, which suggested ANTXR1 as a candidate target via thermal proteome profiling (TPP) assay. Further cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) analysis identified ANTXR1 as a direct target of 8a (K = 2.88 μM). LC-MS/MS, molecule docking and molecular dynamics simulations (MD) demonstrated that the 8-adamantane acetyl in 8a could undergo an acylation reaction with Ser229 of ANTXR1, thereby inhibiting tumor cell proliferation. Therefore, compound 8a is a covalent inhibitor of ANTXR1, and introducing an ester group as the chemical warhead represents a highly effective structural modification strategy in medicinal chemistry.
Liang C, Wang S, Liu X
… +8 more, Wang X, Yuan B, Wang X, Liu W, Wang T, Song C, Yao Y, Duan Y
Eur J Med Chem
· 2026 Oct · PMID 42143940
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The P2X7 receptor (P2X7R) is critically involved in tumor progression by promoting cancer cell proliferation, invasion, metastasis, and immune evasion. Through structure-based virtual screening of the TOPSCIENCE L1000 li...The P2X7 receptor (P2X7R) is critically involved in tumor progression by promoting cancer cell proliferation, invasion, metastasis, and immune evasion. Through structure-based virtual screening of the TOPSCIENCE L1000 library, we identified pixantrone - an FDA-approved agent - as a promising lead compound targeting P2X7R. Leveraging its well-established safety profile and anthraquinone scaffold, we designed and synthesized a novel series of P2X7R antagonists. Among them, the optimized compound 17d displayed potent antagonistic activity (IC = 3.57 μM) and specific binding to P2X7R. In addition, 17d exhibited significant antiproliferative activity against MCF-7 cells (IC = 0.42 μM) and effectively inhibited their invasive and metastatic capabilities. Compound 17d also demonstrated favorable oral bioavailability and pharmacokinetic properties. Moveover, in a murine breast cancer model, 17d significantly suppressed tumor growth and metastasis while promoting the activation of CD4 and CD8 T cells to enhance antitumor immunity. Notably, 17d acted synergistically with anti-PD-1 monoclonal antibody, overcoming resistance to anti-PD-1 therapy. These findings highlight 17d as a promising candidate for P2X7R-targeted cancer therapy and underscore the value of repurposing FDA-approved drugs using structure-based approaches to accelerate the development of safer and more effective anticancer agents.
Wang W, Li Y, Zhang W
… +4 more, Zhang Y, Zhang K, Zhang X, Wang T
Eur J Med Chem
· 2026 Oct · PMID 42142455
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Immune checkpoints (ICs) serve as critical negative regulators of immune responses, which maintain tolerance and limit inflammation. Tumor cells evade immune surveillance by upregulating ICs and accumulating immunosuppre...Immune checkpoints (ICs) serve as critical negative regulators of immune responses, which maintain tolerance and limit inflammation. Tumor cells evade immune surveillance by upregulating ICs and accumulating immunosuppressive molecules in the tumor microenvironment. Immune checkpoint inhibitors, especially monoclonal antibody-based immune checkpoint blockade therapy, demonstrate durable clinical efficacy but face limitations: immune-related adverse events (irAEs), acquired resistance, and limited patient response. Induced proximity strategies, exemplified by proteolysis-targeting chimeras (PROTACs), modulate protein-protein interactions. However, the characteristics of transmembrane ICs present inherent limitations to conventional targeted protein degradation (TPD) technologies like PROTACs. Emerging lysosome-dependent proximity approaches address these limitations and have made significant strides. This review summarizes emerging induced proximity strategies for immune checkpoints modulation, with a focus on design principles, degradation mechanisms, and therapeutic potential, aiming to guide the development of next-generation ICIs for cancer immunotherapy.
Fang L, Qiu F, Wu Y
… +6 more, Li H, Zhang S, Liu SY, Shao J, Shen Y, Chen W
Eur J Med Chem
· 2026 Oct · PMID 42142454
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To circumvent the limitations of aggregation-caused quenching (ACQ) associated with conventional photosensitizers (PSs), we sought to develop PSs based on aggregation-induced emission luminogens (AIEgens). Through molecu...To circumvent the limitations of aggregation-caused quenching (ACQ) associated with conventional photosensitizers (PSs), we sought to develop PSs based on aggregation-induced emission luminogens (AIEgens). Through molecular hybridization of a quinoline-malononitrile (QM) acceptor and a triphenylamine (TPA) unit, along with systematic SAR exploration of N-atom substitutions on the QM core, we generated a series of AIE-active PSs. Among these, A04 emerged as the lead, exhibiting potent Type I ROS generation, a high safety profile (selectivity index >158), and remarkable specificity for the endoplasmic reticulum (ER) (Pearson correlation coefficient = 0.91). Critically, this subcellular localization underpins its mechanism of action: by generating ROS within the ER, A04 induces necroptosis. Consequently, A04 demonstrates robust antitumor PDT activity both in vitro and in a 4T1 murine model. This study thus validates A04 as a therapeutically promising, rationally designed AIEgen-PS.
Jiang Y, Zheng Y, Zou M
… +4 more, Zheng L, Luo Z, Kong L, Wang X
Eur J Med Chem
· 2026 Oct · PMID 42140113
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Inhibiting receptor-interacting serine/threonine-protein kinase 1 (RIPK1) to block necroptosis is a validated therapeutic strategy for inflammatory and neurodegenerative diseases. Herein, we identified the antitumor drug...Inhibiting receptor-interacting serine/threonine-protein kinase 1 (RIPK1) to block necroptosis is a validated therapeutic strategy for inflammatory and neurodegenerative diseases. Herein, we identified the antitumor drug sunitinib as a hit compound with RIPK1 inhibitory activity (IC = 450 nM). Guided by the structural features of the RIPK1 active pocket, sunitinib was systematically modified to design a series of novel derivatives. Screening via in vitro kinase assays and a mouse L929 fibroblast necroptosis model yielded compound 5e (encoded KWJY-5e), a highly potent RIPK1 inhibitor with an IC of 92 nM (5-fold more active than sunitinib). In L929 cells induced to undergo necroptosis with mouse tumor necrosis factor-α (mTNF-α)/Z-VAD-FMK, 5e exhibited robust anti-necroptotic activity (EC = 450 nM). Mechanistically, 5e pretreatment reduced the phosphorylation of RIPK1, RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL), suppressed necrosome formation, and preserved mitochondrial/lysosomal function and cell membrane integrity. In vivo, 5e alleviated hypothermia and multi-organ injury in a mouse model of mTNF-α-induced systemic inflammatory response syndrome (SIRS). Although 5e retains some multi-kinase inhibitory activity, its improved RIPK1 potency and in vivo efficacy support further optimization.
Nie H, Xiang J, Wang N
… +6 more, Liu X, Zhang S, Yang Q, Zeng H, Guo B, Liu Y
Eur J Med Chem
· 2026 Oct · PMID 42140112
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In this study, we designed and synthesized a new ligand, FMPIP (2-(3-fluoro-2-methylphenyl)-1H-imidazo[4,5-f][1,10]phenanthroline), and its three cyclometalated iridium(III) complexes: [Ir(ppy)(FMPIP)](PF) (Ir3a, ppy = 2...In this study, we designed and synthesized a new ligand, FMPIP (2-(3-fluoro-2-methylphenyl)-1H-imidazo[4,5-f][1,10]phenanthroline), and its three cyclometalated iridium(III) complexes: [Ir(ppy)(FMPIP)](PF) (Ir3a, ppy = 2-phenylpyridine), [Ir(bzq)(FMPIP)](PF) (Ir3b, bzq = benzo[h]quinoline), and [Ir(piq)(FMPIP)](PF) (Ir3c, piq = 1-phenylisoquinoline). We evaluated antiproliferative activity of Ir3a, Ir3b and Ir3c against hepatocellular carcinoma cell lines (Huh7, HepG2, SK-Hep1, HCCLM3) using 3-(4,5-dimethylthiazole-2-yl)-diphenyltetrazolium bromide (MTT) assay. Ir3a-Ir3c exhibited negligible cytotoxicity toward all tested cell lines, each with half-maximal inhibitory concentration (IC) values > 100 μM, which was caused by poor solubility of Ir3a, Ir3b and Ir3c in phosphate-buffered saline (PBS). To overcome this limitation, we encapsulated Ir3a-Ir3c into liposomes to produce Ir3alp, Ir3blp and Ir3clp. Ir3alp, Ir3blp and Ir3clp significantly enhanced antiproliferative potency (IC < 5.0 μM). To further enhance anticancer efficacy, we used three kinds of targeted functional liposome to encapsulate Ir3a to form Ir3aT1lp, Ir3aT2lp and Ir3aT3lp. Against Huh7 cells, Ir3aT1lp, Ir3aT2lp and Ir3aT3lp showed IC values of 1.34 ± 0.04 μM, 1.26 ± 0.01 μM, and 1.23 ± 0.07 μM, respectively. Mechanistic studies revealed that Ir3alp, Ir3aT3lp, Ir3blp and Ir3clp trigger intracellular reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential and apoptosis, we further observed some markers consistent with ferroptosis. Ir3aT3lp displayed potent antitumor efficacy with a tumor growth inhibition rate of 64.90%, simultaneously, they induce an increment of CD8 T cells. These results show that Ir3alp, Ir3aT3lp, Ir3blp and Ir3clp induced ferroptosis to stimulate immune response to elevate the CD8 T cells to exert antitumor efficiency.
The fibroblast growth factor receptors (FGFRs) have garnered considerable attention as promising therapeutic targets in oncology, given their pivotal involvement in regulating cell proliferation, differentiation, and var...The fibroblast growth factor receptors (FGFRs) have garnered considerable attention as promising therapeutic targets in oncology, given their pivotal involvement in regulating cell proliferation, differentiation, and various other physiological processes. In this study, we have designed and synthesized a series of FGFR inhibitors featuring the 3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one scaffold as a core structural motif. Notably, among these derivatives, compound 1a emerged as a potent inhibitor of four distinct FGFR subtypes, demonstrating superior efficacy in suppressing the proliferation of Huh7 hepatocellular carcinoma cells compared to BGJ398, a clinically validated FGFR inhibitor. In preclinical evaluations, 1a exhibited remarkable pharmacokinetic properties (oral bioavailability = 66.9%). In Balb/c mice bearing Huh7 xenografts, 1a achieved a 90.5% tumor growth inhibition rate at a dose of 50 mg/kg, with no discernible signs of systemic toxicity. Collectively, these findings indicate that 1a holds great potential as a broad-spectrum FGFR inhibitor for cancer treatment, supporting its further development in clinical settings.