Rui X, Sun S, Ding Y
… +8 more, Li Y, Zhao X, Hu F, Zhou Z, Zhang N, Zhang C, Cheng C, Ji B
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42113227
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The P2X7 receptor (P2X7R) is an imaging biomarker of glioblastoma-associated microglia/macrophages (GAMMs), yet no SPECT tracer is currently available for GAMM imaging. Guided by the high-affinity P2X7R scaffold JNJ-6441...The P2X7 receptor (P2X7R) is an imaging biomarker of glioblastoma-associated microglia/macrophages (GAMMs), yet no SPECT tracer is currently available for GAMM imaging. Guided by the high-affinity P2X7R scaffold JNJ-64413739 and molecular docking, we designed two radioiodination-ready analogues, FJR01 and FJR02. Compounds were screened using homogenates from cell lines stably expressing mouse or human P2X7R; FJR01 was prioritised (hP2X7R, = 8.8 nM). Radioiodination afforded [I]FJR01 in high radiochemical yield (95%) with excellent stability. In normal mice, biodistribution showed high brain uptake and rapid clearance. In a rat C6 glioma model, SPECT demonstrated focal tumour accumulation, which was corroborated by autoradiography; immunofluorescence confirmed P2X7R expression in GAMMs. Histopathology (H&E) and mouse-to-human dosimetry supported a favourable safety profile and the clinical translation potential of [I]FJR01. In addition, [I]FJR01 is well suited as a probe for competitive binding assays to screen next-generation P2X7R-targeted ligands.
Lee SS, Kim JH, Bang K
… +5 more, Yu J, Kim YG, Kim SY, Lee IS, Yoo YC
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42113121
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PTP1B is a key negative regulator of insulin and leptin signalling and a promising therapeutic target for metabolic dysfunction, yet no clinically approved inhibitor exists due to selectivity and bioavailability challeng...PTP1B is a key negative regulator of insulin and leptin signalling and a promising therapeutic target for metabolic dysfunction, yet no clinically approved inhibitor exists due to selectivity and bioavailability challenges. To identify novel natural PTP1B inhibitors from and evaluate their efficacy in reversing hormonal resistance and redox imbalances in skeletal muscle and hepatic models. Four flavonoids (EC2-EC5) were assessed via PTP1B inhibition assays, molecular docking, glucose uptake, qRT-PCR, and NAD(H)/NADP(H) quantification in palmitate-treated C2C12 myotubes and Hepa1c1c7 hepatocytes. All compounds potently inhibited PTP1B (IC < 5.4 µM). EC2 showed the strongest activity and normalised redox imbalances, while EC5 exhibited the highest binding affinity and restored multi-hormone responsiveness, potentially through PTP1B inhibition combined with AMPK pathway engagement. EC2 and EC5 represent promising natural PTP1B inhibitors partially restoring metabolic homeostasis and multi-hormone responsiveness , highlighting their potential for insulin resistance and metabolic syndrome.
Gallo R, Scarano A, Gianquinto E
… +8 more, Franzini G, Antonini G, Montalbano S, Palmieri C, Conti P, Spyrakis F, Borsari C, Bruno S
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42112964
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Prostate cancer (PCa) remains a major global health burden. Although androgen deprivation and receptor-targeted therapies initially benefit patients, resistance often leads to metastatic castration-resistant prostate can...Prostate cancer (PCa) remains a major global health burden. Although androgen deprivation and receptor-targeted therapies initially benefit patients, resistance often leads to metastatic castration-resistant prostate cancer, with limited treatment options. Aldehyde dehydrogenase 7A1 (ALDH7A1) is an emerging oncogenic driver of PCa, but selective inhibitors are lacking. Here, we report irreversible ALDH7A1 inhibitors targeting the catalytic Cys330, identified from a library of 3-bromo-4,5-dihydroisoxazole derivatives. These compounds show minimal inhibition of ALDH4A1 and GAPDH, supporting selectivity for ALDH7A1. Compounds and reduced DU145 cell viability (low μM IC), impaired migration, and altered the cell cycle. No significant effects were observed in LNCaP cells (low ALDH7A1 expression) or Hs27 fibroblasts. Treatment of DU145 cells resulted in the inhibition of intracellular ALDH activity and accumulation of malondialdehyde, consistent with increased oxidative stress. These findings validate ALDH7A1 as a druggable target and introduce a new chemical space for selective covalent ALDH inhibitors in oncology.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42109224
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Chitinase-3-like protein 1 (CHI3L1) is a key driver of glioblastoma (GBM) progression and an emerging therapeutic target. Building on the CHI3L1 inhibitor , we optimised the scaffold through medicinal chemistry to assess...Chitinase-3-like protein 1 (CHI3L1) is a key driver of glioblastoma (GBM) progression and an emerging therapeutic target. Building on the CHI3L1 inhibitor , we optimised the scaffold through medicinal chemistry to assess structure-property relationships and improve pharmacokinetics. Using microscale thermophoresis (MST) and computational studies, we validated , which exhibits a CHI3L1 binding affinity () of 13.22 µM. Notably, overcomes previous developability hurdles by achieving a kinetic solubility of 758 µM, a five-fold improvement over . It further demonstrates high metabolic stability across species and no hERG inhibition. In 3D GBM spheroid models, significantly reduced tumour viability, mass, and migration, exceeding the efficacy of prior analogues. Collectively, these findings establish as a CHI3L1 inhibitor with a superior pharmacokinetic profile and robust functional activity, marking it as a promising candidate for further GBM drug development.
Zheng L, Wei B, Pang J
… +4 more, Yang Y, Zhang M, Ma K, Lu S
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 42059810
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Structural modification of bioactive natural products plays a vital role in the development of new drugs. Herein, we report the design and synthesis of twelve new tyrcinnamin derivatives (-, -, -, , and ) using tyrcinnam...Structural modification of bioactive natural products plays a vital role in the development of new drugs. Herein, we report the design and synthesis of twelve new tyrcinnamin derivatives (-, -, -, , and ) using tyrcinnamin methyl ester () as a lead. biological investigation indicated that, unlike the lead (), which is a bacteriostat, exhibited significant bactericidal activity against and methicillin-resistant (MRSA). Mechanistic studies indicated that the bactericidal effect of might induced by the membrane-disrupting and reactive oxygen species (ROS) generation. investigation with a larvae infection model revealed that significantly inhibited the growth of MRSA, therefore enhancing the survival rate of the MRSA-infected larvae. The strong antibacterial activity, excellent safety profile, and good solubility of make it a promising candidate for the development of new bactericides.
Wu P, Tian Z, Shen W
… +9 more, Xun Q, Tian Y, Li H, Yang B, Chang S, Huang W, Wang Z, Ding K, Ma D
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41910341
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Although FGFR2 is a well-validated oncogenic target, no selective FGFR2 inhibitors have been approved for clinical use. In this study, we report the discovery of 2-pyrazolo[3,4-]pyrimidin-4-amine derivative as novel, irr...Although FGFR2 is a well-validated oncogenic target, no selective FGFR2 inhibitors have been approved for clinical use. In this study, we report the discovery of 2-pyrazolo[3,4-]pyrimidin-4-amine derivative as novel, irreversible FGFR2 inhibitors. The optimal compound, , potently inhibited FGFR2 with an IC value of 13.59 nM and demonstrated exceptional selectivity over FGFR1, FGFR3, and FGFR4. Covalent binding to the target was confirmed by mass spectrometry. In cellular models, exhibited potent and selective antiproliferative effects against FGFR2-driven cancer cells, effectively suppressed downstream FGFR2 signalling and induced cancer cell apoptosis. Notably, it showed minimal activity in non-FGFR2-dependent cells. This work presents a new class of selective FGFR2 inhibitors based on a novel scaffold, offering promising lead compounds for the development of FGFR2-target therapies.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41885448
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The degradation of overexpressed proteins has emerged as a promising strategy for halting disease progression, particularly in cancer. Traditional small-molecule drugs often face limitations in the elimination of pathoge...The degradation of overexpressed proteins has emerged as a promising strategy for halting disease progression, particularly in cancer. Traditional small-molecule drugs often face limitations in the elimination of pathogenic proteins, leading to the development of targeted protein degradation (TPD) approaches. A prominent strategy for TPD is the proteolysis targeting chimaera (PROTAC) which harnesses the ubiquitin proteasome system, the cell's innate degradation machinery, to degrade proteins of interest (POIs). In this review, we will focus on the design and synthetic strategies that led the advancements of PROTACs as a cancer therapy for the targeted degradation of poly ADP-ribose polymerases (PARPs), glutathione peroxidase 4 (GPX4) and epigenetic regulators. We also aim to address the prevailing challenges in PROTAC development and clinical translation, namely target diversification, oral bioavailability, stability, degradation efficiency, and optimising multivalent binding.
Bianconi E, Lampitella EA, Nigro F
… +8 more, Rossi L, Zambri F, Fava S, Marone M, Porzio E, Macchiarulo A, Manco G, Marinozzi M
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41885432
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A plethora of studies have demonstrated the pathophysiological roles played by paraxonase 2 (PON2) in oxidative stress control, inhibition of apoptosis, infections, and the progression of various types of malignancies. T...A plethora of studies have demonstrated the pathophysiological roles played by paraxonase 2 (PON2) in oxidative stress control, inhibition of apoptosis, infections, and the progression of various types of malignancies. The continuous interest in PON2 has not gone hand in hand with the development of its inhibitors. Indeed, only one inhibitor for PON2, namely TQ416, is known, although neither its preparation nor a systematic structure-activity relationship analysis has been so far reported. Herein, we outline the first study aimed at the definition of structure-activity relationships of TQ416 by the preparation of a small library of its analogues. Successfully, we identified some [1,2,4]triazolo[4,3-]quinoline derivatives more potent than TQ416 as PON2 inhibitors, and among them one endowed with an IC value in the nanomolar range. We tested the parent TQ416 and its most effective congener in cells showing their effectiveness and complex behaviour.
Lao K, Li Y, Xiao Y
… +9 more, Sun Y, Dai Y, Li H, Yang Y, Zhang Y, Wang J, Li W, Gou X, Guan L
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41873153
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Given the multifactorial aetiology of Alzheimer's disease, multi-target strategies have emerged as a promising therapeutic approach. In this study, we designed and synthesised a series of ferulic acid carbamate derivativ...Given the multifactorial aetiology of Alzheimer's disease, multi-target strategies have emerged as a promising therapeutic approach. In this study, we designed and synthesised a series of ferulic acid carbamate derivatives to selectively inhibit BuChE and stimulate Nrf2 pathway. The biological evaluation revealed that compound and were the most potent, exhibiting over 150-fold selectivity for BuChE. Also, , and significantly reversed both HO and Aβ-induced toxicity in HT22 cells. These compounds were further shown to eliminate ROS accumulation induced by Aβ and upregulated HO-1 and GCLM by promoting the nuclei translocation of Nrf2. In Aβ transgenic , three lead compounds alleviated Aβ-induced paralysis and cognitive deficits. study revealed that compound fitted well into the active sites of BuChE and Keap1 while maintaining favourable CNS drugability. This dual strategy of cholinesterase inhibition and oxidative stress mitigation is a promising approach for novel AD therapeutics.
Tambascia C, Silva JC, Dos Reis BC
… +11 more, Camilo CFS, Tairum Junior CA, Hancio T, Correia VG, Pilli RA, de Godoy AS, Laleu B, Sforça ML, Rocco SA, Benedetti CE, Mercaldi GF
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41848420
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Aminoacyl-tRNA synthetases have been widely exploited as targets for antiparasitic and antifungal inhibitors; however, they have received little attention as targets in multidrug-resistant (MDR) bacteria. Here we describ...Aminoacyl-tRNA synthetases have been widely exploited as targets for antiparasitic and antifungal inhibitors; however, they have received little attention as targets in multidrug-resistant (MDR) bacteria. Here we describe the biochemical characterisation of Prolyl-tRNA synthetase from (KpProRS), highlighting its ligase and proofreading activities. Distinct classes of ProRS inhibitors were evaluated against KpProRS but only halofuginone (HF) strongly modulated KpProRS activity. A new HF analog (Cpd-6) was developed and exhibited superior inhibitory activity against KpProRS relative to HF but low efficacy against MDR , despite good antimicrobial activity against and Further studies revealed that Cpd-6 resistance in is mainly mediated by efflux pump activity, which could be counteracted by efflux pump inhibitors. These findings therefore reinforce KpProRS as a target for antimicrobial development and highlight the therapeutic potential of combining HF analogues with efflux pump inhibitors to fight Gram-negative MDR pathogens.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41840942
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To address the imbalance between antibacterial potency and developability in cephalosporin discovery against , we developed a comprehensive screening strategy guided by the principle of maximum drug-likeness. An integrat...To address the imbalance between antibacterial potency and developability in cephalosporin discovery against , we developed a comprehensive screening strategy guided by the principle of maximum drug-likeness. An integrated evaluation framework was established, consisting of 33 independent predictive submodels across five dimensions: physicochemical properties, pharmacokinetics, safety, efficacy, and stability. This framework was combined with a five-fold property-spectrum scoring mechanism () to enable multidimensional and quantitative prioritisation of candidates based on overall developability. Application of this strategy to the eMolecules library yielded 15 high-potential candidates. Experimental results showed compound M3 as the lead molecule, exhibiting notable antibacterial activity against (minimum inhibitory concentration [MIC] = 16 μg/mL). Molecular analyses further demonstrated that M3 achieved superior binding stability relative to the reference drug Cefaclor through a multimodal, high-affinity interaction network with the target protein. This strategy reduces late-stage attrition risk and provides a robust paradigm for rational antibacterial drug discovery.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41837490
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The Warburg effect, a hallmark of cancer, positions lactate dehydrogenase (LDH) as a key therapeutic target. Mammals possess three LDH isozymes (LDH-A, LDH-B, LDH-C) with distinct properties. This review critically re-ev...The Warburg effect, a hallmark of cancer, positions lactate dehydrogenase (LDH) as a key therapeutic target. Mammals possess three LDH isozymes (LDH-A, LDH-B, LDH-C) with distinct properties. This review critically re-evaluates the simplistic 'aerobic-anaerobic' paradigm, emphasizing that all isozymes catalyze reversible pyruvate-lactate conversion and contribute to tumor metabolism in a context-dependent manner. While LDH-A inhibition is a primary focus, challenges include metabolic plasticity and compensatory LDH-B upregulation. LDH-B plays a critical role in mitochondrial lactate oxidation. We highlight LDH-C as a compelling cancer/testis antigen target. Beyond glycolysis, LDH-C exhibits unique substrate promiscuity, generating oncometabolites like s-2-hydroxyglutarate from α-ketoglutarate. Its structural distinctions and restricted normal tissue expression offer opportunities for highly selective therapy. A comprehensive understanding of all three isozymes is essential for developing effective metabolic interventions against cancer.
Yang X, Yang S, Lin G
… +5 more, Chen S, Jiang H, Wang Y, Zhang Y, Zhang X
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41800759
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Aberrant activation of YAP-TEAD4 drives tumorigenesis, progression, and chemoresistance. Disrupting their interaction serves as an alternative anticancer strategy, with peptides better adapting to the large, flat interac...Aberrant activation of YAP-TEAD4 drives tumorigenesis, progression, and chemoresistance. Disrupting their interaction serves as an alternative anticancer strategy, with peptides better adapting to the large, flat interaction interface. In this study, the peptides 1-4 were screened from the peptide database via pharmacophore modelling, molecular docking, and interaction analysis. Subsequently, affinity experiments showed that among the peptides 1-4, peptide-4 possessed the lowest values ( = 5.08 ± 0.42 nM) measured by MST and exhibited the binding affinity for TEAD4. MD simulations further demonstrated that peptide-4 stably bound to the TEAD4. MTT assays showed that peptide-4 suppressed AML-193 cell viability with an IC of 0.65 ± 0.04 μM. RT-qPCR assays demonstrated that Peptide-4 significantly downregulated the mRNA expression levels of and . In conclusion, the data demonstrated that the peptide-4 may serve as a promising candidate to disrupt the YAP-TEAD4 interaction and enhance biological activity in AML-related cellular models.
Zhao Y, Sun H, Yan Z
… +7 more, Wang Y, Li S, Guo Y, Miao G, Wang T, Zhang L, Song C
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41797643
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Fluorescently labelled small molecule probes (fluorescent probes) play an important role in cell imaging and are often used in combination with light-affinity probes to determine the subcellular localisation of target pr...Fluorescently labelled small molecule probes (fluorescent probes) play an important role in cell imaging and are often used in combination with light-affinity probes to determine the subcellular localisation of target proteins. To investigate the target proteins of 18-glycyrrhetinic acid (18-GA), which regulates the macrophage inflammatory response, we designed and synthesised three types of fluorescent probes. We analysed its structure-activity relationship by evaluating the biological activity and screening for fluorescent probes with high activity. Our results showed that modifying C-3 hydroxyl and C-30 carboxyl groups enhanced the anti-inflammatory activity of 18-GA, and found that two preferred probes had similar effects on LPS-induced, inflammation-related factor release (IL-1β, TNF-α, IL-6, HDAC8, P-STAT3, and SOCS3) to those of 18-GA. Fluorescence signals of the preferred probes and were observed in the cytoplasm. The above results indicated that the anti-inflammatory site of 18-GA may be located in proteins in the cytoplasm, which would provide useful information for research on the anti-inflammatory targets of 18-GA.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41784256
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FMS-like tyrosine kinase 3 (FLT3/CD135) regulates haematopoiesis and is frequently mutated as FLT3-internal tandem duplication (FLT3-ITD) in acute myeloid leukaemia (AML), associated with poor prognosis. Although FLT3 in...FMS-like tyrosine kinase 3 (FLT3/CD135) regulates haematopoiesis and is frequently mutated as FLT3-internal tandem duplication (FLT3-ITD) in acute myeloid leukaemia (AML), associated with poor prognosis. Although FLT3 inhibitors show clinical benefits, resistance remains a challenge. This study hypothesises that antibody-drug conjugate (ADC) efficacy depends on distinct FLT3 trafficking mechanisms in FLT3-wt and FLT3-ITD cells. Confocal imaging showed that in THP-1 (FLT3-wt) cells, FLT3 mAb trafficked to lysosomes, while in MV4-11 (FLT3-ITD) cells, it accumulated in the Golgi. To evaluate the impact of this trafficking difference, we synthesised an anti-FLT3 mAb-MMAE, linked via a Val-Cit-PAB linker at the Fc N-glycan, which exhibited lower cytotoxicity in MV4-11 than THP-1 cells, indicating that the impaired lysosomal trafficking of FLT3-ITD limits drug release and reduces ADC potency. These findings highlight that effective lysosomal targeting is essential for ADC activity and suggest that optimising linker design or restoring lysosome trafficking may enhance FLT3-targeted ADC in AML.
Ye C, Chen Z, Jiang J
… +5 more, Li J, Kong R, Liu S, Chen X, Xu Z
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41725379
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A series of oxadiazole-based dual inhibitors targeting GSK3 and HDAC6 were rationally designed by integrating key pharmacophores into a single molecule. Among these derivatives, 4-(((5-(benzo[][1, 3]dioxol-5-yl)-1,3,4-ox...A series of oxadiazole-based dual inhibitors targeting GSK3 and HDAC6 were rationally designed by integrating key pharmacophores into a single molecule. Among these derivatives, 4-(((5-(benzo[][1, 3]dioxol-5-yl)-1,3,4-oxadiazol-2-yl)thio)methyl)--hydroxybenzamide () was identified as the most potent compound with IC of 5.50, 69 nM and 88 nM against HDAC6, GSK3 and GSK3, respectively. also exhibited potent cytotoxicity against the AGS cancer cell line, with IC values in the submicromolar range. Molecular docking simulation confirmed that fitted well into the active sites of both HDAC6 and GSK3. These findings establish compound as a promising candidate for further evaluation.
Li X, Wang M, Li S
… +7 more, Xie W, Jin R, Xie Y, Zhou S, Xiong L, Yang N, Zhou S
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41712261
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To develop eco-friendly pesticides with novel modes of action for insect management, a series of dual-chiral -cyano sulfilimine-substituted anthranilic diamides were designed and synthesised , and their insecticidal acti...To develop eco-friendly pesticides with novel modes of action for insect management, a series of dual-chiral -cyano sulfilimine-substituted anthranilic diamides were designed and synthesised , and their insecticidal activities were evaluated against () and (). Most target compounds exhibited potent insecticidal activity against . Notably, compounds and demonstrated near-complete inhibition at 0.1 mg/L, achieving efficacy comparable to the commercial standard chlorantraniliprole (CHL). Furthermore, and outperformed CHL against , suggesting enhanced specificity. matchedCHL's efficacy against . Specific target compounds, including and , emerged as potential modulators of insect ryanodine receptor (RyR). Molecular docking revealed that probably formed three hydrogen bonds with RyR binding pocket and exhibited stronger binding affinity than CHL (two hydrogen bonds). These findings provide a structural foundation for rational design of novel chiral sulfiliminyl RyR-targeting insecticides.
Hmone NY, Tian X, Zhou D
… +6 more, Min Z, Zhao Y, Wang S, Chen FE, Wang Z, Zhang X
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41711747
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ABCB1-mediated drug efflux is a key determinant of multidrug resistance (MDR) in cancer. To overcome this mechanism, a series of thiol-substituted aminocoumarin-derived, coumarin-containing triazolo[1,5-a]pyrimidine deri...ABCB1-mediated drug efflux is a key determinant of multidrug resistance (MDR) in cancer. To overcome this mechanism, a series of thiol-substituted aminocoumarin-derived, coumarin-containing triazolo[1,5-a]pyrimidine derivatives (5a-5s) was synthesised, and compound 5r (NYH-707) was identified as the most potent ABCB1 inhibitor. NYH-707 markedly restored paclitaxel sensitivity in SW620/Ad300 MDR cells, reducing the IC from 4.55 ± 0.73 µM to 0.011 ± 0.002 µM (reversal factor = 413.6). Molecular docking predicted strong binding (-9.7 kcal/mol) through hydrogen bonding with LYS-826 and SER-880 and π-π stacking with PHE-994. CETSA confirmed direct ABCB1 engagement, while drug-accumulation assays demonstrated inhibition of ABCB1-mediated efflux. In vivo, co-administration of NYH-707 and paclitaxel significantly suppressed SW620/Ad300 xenograft growth without detectable systemic toxicity. These findings indicate that NYH-707 acts as a potent and selective ABCB1 modulator capable of reversing MDR likely by modulating ABCB1 conformational dynamics, thereby enhancing chemotherapeutic efficacy in resistant tumours.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41711685
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In studying the roles of reactive oxygen species (ROS) in various biological processes, the availability of appropriate cell culture models is critical. Addition of HO to cells is commonly used to simulate oxidative stre...In studying the roles of reactive oxygen species (ROS) in various biological processes, the availability of appropriate cell culture models is critical. Addition of HO to cells is commonly used to simulate oxidative stress. In doing so, generation of highly reactive oxygen species (hROS) in cell culture is used as an indication of successful model creation. The validity of such a model is predicated on the assumption that hROS formation is the result of cellular biochemical processes and not from the medium. However, we observed a significant level of hROS in various culture media alone upon HO addition, raising questions about the validity of such models and suggesting a "Trojan Horse" role for such media in compromising the data. Given the wide-spread use of the said method, we urge caution in analysing information gained from such models in redox mechanistic studies.