Sharma R, Rana M, Thakur A
… +4 more, Ojha R, Mousavi SM, Dhingra A, Nepali K
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41693699
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Palladium-catalysed reactions have emerged as indispensable tools in medicinal chemistry, enabling the precise construction of C-C and C-N bonds across a wide spectrum of drug-like molecular frameworks. This manuscript c...Palladium-catalysed reactions have emerged as indispensable tools in medicinal chemistry, enabling the precise construction of C-C and C-N bonds across a wide spectrum of drug-like molecular frameworks. This manuscript comprehensively examines advances reported over the past five years in palladium-catalysed methodologies applied to epigenetic drug discovery. The mechanistic diversity and synthetic adaptability of palladium catalysts for accessing scaffolds addressing the epigenetic targets have been highlighted. The robust drug design strategies and activity profile of the generated small molecule epigenetic inhibitors through palladium-assisted synthetic protocol are also presented in this compilation. Particular emphasis is placed on understanding the influence of ligand structure, base selection, and solvent optimisation in modulating catalyst reactivity. Collectively, this review offers a practical and forward-looking framework for the design and synthesis of next-generation epigenetic anticancer therapeutics (selective/non-selective/hybrid-inhibitors and degraders/PROTACS).
He ML, Wang ZH, Yao X
… +8 more, Ye LL, Du BQ, Wang CC, Chen YH, Wang XX, Luo H, Gao Y, Ye XY
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41693691
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PARP1 inhibitors are FDA-approved for BRCA1/2-mutated breast cancer but show limited efficacy in wild-type cancers and face resistance issues. To overcome these, we designed novel 6,7-dihydro-5-pyrrolo[3,4-]pyrimidine-ba...PARP1 inhibitors are FDA-approved for BRCA1/2-mutated breast cancer but show limited efficacy in wild-type cancers and face resistance issues. To overcome these, we designed novel 6,7-dihydro-5-pyrrolo[3,4-]pyrimidine-based compounds integrating PARP1 inhibitor pharmacophores with the ATR inhibitor AZD6738 scaffold. Substituent modifications influenced PARP1 and ATR selectivity, yielding dual inhibitors or selective PARP1 inhibitors. Compound , the lead candidate, exhibited potent dual inhibition (IC < 20 nM) and strong antitumor effects in MDA-MB-231 (IC < 0.048 μM) and MDA-MB-468 (IC: 0.01 μM) cell lines . Mechanistically, arrested cell cycle progression, induced apoptosis, inhibited colony formation and migration, and suppressed DNA damage repair pathways, outperforming combined Niraparib and AZD6738. These findings underscore the therapeutic potential of PARP1/ATR dual inhibitors for breast cancer and support further investigation.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41693684
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Diethyl phthalate (DEP), a common plasticiser and endocrine disruptor, has been linked to cancer, but its role in osteosarcoma (OS) remains unclear. This study integrated network toxicology, transcriptomics, protein-prot...Diethyl phthalate (DEP), a common plasticiser and endocrine disruptor, has been linked to cancer, but its role in osteosarcoma (OS) remains unclear. This study integrated network toxicology, transcriptomics, protein-protein interaction (PPI) analysis, machine learning, molecular docking, molecular dynamics (MD), single-cell RNA sequencing (scRNA-seq), and external validation to investigate DEP-related mechanisms in OS. We identified 45 DEP-responsive genes enriched in extracellular matrix-related pathways. PPI network analysis revealed 11 hub genes, of which LASSO, SVM-RFE, and Boruta algorithms consistently prioritised P4HA2, COL18A1, and COL10A1. Docking and MD simulations supported stable binding of DEP to P4HA2 and COL18A1 via hydrogen bonds and hydrophobic interactions. scRNA-seq demonstrated celltype-specific expression of these genes. Validation cohorts confirmed their upregulation in OS, with AUC values up to 0.950. These findings suggest that DEP may promote OS progression by targeting extracellular matrix remodelling, offering new diagnostic biomarkers and hypothesis-generating evidence for environmental osteocarcinogenesis.
Liu S, Lao Y, Cheng L
… +10 more, Xiao X, Ma L, Wang W, Zhao K, Li W, Zhou Z, Li Q, Tao Y, Liu S, Dong Z
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41665114
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Docetaxel (DTX) resistance is the main cause of treatment failure in castration-resistant prostate cancer (CRPC). Pyrroline-5-carboxylic acid reductase 1 (PYCR1) is an enzyme involved in proline metabolism. It is highly...Docetaxel (DTX) resistance is the main cause of treatment failure in castration-resistant prostate cancer (CRPC). Pyrroline-5-carboxylic acid reductase 1 (PYCR1) is an enzyme involved in proline metabolism. It is highly expressed in various cancers and promotes malignant progression, yet its role in DTX resistance in prostate cancer remains unclear. In this study, bioinformatics analyses and / experiments demonstrated that interfering with PYCR1 expression modulates the sensitivity of prostate cancer cells to DTX. Subsequently, via structure-based virtual screening, molecular dynamics simulations, and cellular thermal shift assay (CETSA), emodin-an anthraquinone compound-was identified as a PYCR1-targeting agent. Collectively, these findings suggest that PYCR1 may serve as a key target mediating DTX resistance in prostate cancer, and the emodin-DTX combination provides a promising potential clinical strategy to overcome such resistance. Finally, its functions and safety were also verified through experiments.
Li W, Guo Y, Wang X
… +3 more, Yang C, Zhu J, Cao Z
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41645766
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Alzheimer's disease (AD) still lacks therapies that definitively halt its progression. Dual AChE/MAO-B inhibitors offer a promising strategy to address both symptoms and pathology. Here, we designed and synthesised a ser...Alzheimer's disease (AD) still lacks therapies that definitively halt its progression. Dual AChE/MAO-B inhibitors offer a promising strategy to address both symptoms and pathology. Here, we designed and synthesised a series of donepezil-safinamide hybrids. The optimised compound was identified as a potent inhibitor of AChE (IC = 1.70 μM) and MAO-B (IC = 0.18 μM). Mechanistic studies indicated that acts as a reversible mixed-type inhibitor of AChE and a competitive reversible inhibitor of MAO-B. Molecular docking and molecular dynamic simulations revealed that could strongly and stably bind to MAO-B and AChE mainly through van der Waals interactions. Moreover, compound demonstrated effective blood-brain barrier penetration, exhibited suitable stability in mouse plasma and brain homogenate, and showed a favourable safety profile both and . Furthermore, could attenuate AD-related symptoms and exert hippocampal neuroprotection effect , highlighting its promise as an anti-AD candidate.
Baig MH, Jo YS, Nale SD
… +6 more, Kim CJ, Park J, Ha J, Moon B, Ryu S, Dong JJ
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41645749
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KRAS-G12D mutations are common drivers of pancreatic and colorectal cancers, yet effective targeted therapies remain limited. This study describes the design, synthesis, and biological evaluation of two novel KRAS-G12D i...KRAS-G12D mutations are common drivers of pancreatic and colorectal cancers, yet effective targeted therapies remain limited. This study describes the design, synthesis, and biological evaluation of two novel KRAS-G12D inhibitors, GD-2 and GD-4. Both compounds exhibited strong antiproliferative activity in AGS and ASPC1 cancer cell lines, with IC₅。 values ranging from 0.2 to 1.8 µM. The protein binding assay also demonstrated high affinity for KRAS-G12D, with dissociation constants (Kd) of 146 nM for GD-2 and 3.18 nM for GD-4. Mechanistic investigations revealed that both compounds significantly reduced downstream, as evidenced by a clear decrease in phospho-ERK expression. Additionally, molecular dynamics simulations confirmed stable binding interactions within the KRAS-G12D pocket. Collectively, these findings identify GD-2 and GD-4 as promising therapeutic candidates for KRAS-G12D-driven cancers.
Wu C, Ding Y, Liu X
… +3 more, Gao S, Wang X, Tang W
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41645747
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Thymol, an isomer of carvacrol, exhibits anti-A activity. Thymol carbamates were designed, and their inhibition on cholinesterase (ChE) activity was assessed and analysed, among them, , , and bearing cyclic amines exhi...Thymol, an isomer of carvacrol, exhibits anti-A activity. Thymol carbamates were designed, and their inhibition on cholinesterase (ChE) activity was assessed and analysed, among them, , , and bearing cyclic amines exhibited nanomolar inhibitory activity with IC values of 13, 3.6, 47, and 12 nM. bearing a piperidinyl moiety demonstrated nanomolar BuChE inhibition (IC = 3.6 nM), >2,500-fold selectivity over AChE, and pseudo-irreversible kinetics ( = 0.25 μM, = 0.98 min). exhibited low cytotoxicity, crossed the blood-brain barrier, and protected neurons against HO-induced damage. In A-induced AD mice, (10 mg/kg) greatly enhanced cognitive abilities in MWM tests, reduced brain A levels, and restored hippocampal neuron density. These results highlight as a potent, brain-penetrant BuChE inhibitor with therapeutic potential for AD.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41645730
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Nrf2 is recognised as an attractive therapeutic target for oxidative stress-related disorders through its regulation of antioxidant gene transcription. Direct inhibition of Keap1-Nrf2 protein-protein interaction represen...Nrf2 is recognised as an attractive therapeutic target for oxidative stress-related disorders through its regulation of antioxidant gene transcription. Direct inhibition of Keap1-Nrf2 protein-protein interaction represents a promising strategy to modulate Nrf2 activity. Herein, we report the discovery of meta-substituted bis(arylsulfonamido)benzene derivatives using a molecular hybridisation strategy based onpotent inhibitors and . Among the initial hybrids, demonstrated good potency in the FP assay, making it a suitable lead for SAR optimisation. Our study found was the most potent analog, showing IC values of 183.4 nM in the FP assay and 107.5 nM in the TR-FRET assay. It also demonstrated excellent metabolic stability, with 93.9% remaining after a 30 minute-incubation in human liver microsomes. Collectively, these results highlight as a non-covalent Keap1-Nrf2PPI inhibitor, with balanced potency and metabolic stability, supporting its potential as a tractable scaffold for further optimisation to modulate the Nrf2 pathway.
Yang T, Zhang Y, Liu P
… +4 more, Qi P, Li X, Zhi W, Zhao L
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41601150
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Indole is a privileged heteroaromatic scaffold in medicinal chemistry, characterised by its unique physicochemical properties, hydrogen-bonding potential, and bioisosteric versatility. Over the past decades, numerous ind...Indole is a privileged heteroaromatic scaffold in medicinal chemistry, characterised by its unique physicochemical properties, hydrogen-bonding potential, and bioisosteric versatility. Over the past decades, numerous indole-containing drugs have been approved by the Food and Drug Administration (FDA), spanning diverse therapeutic areas including oncology, infectious diseases, gastrointestinal disorders, neurological conditions, and cardiovascular diseases. This review provides a comprehensive survey of FDA-approved indole-based drugs, with particular emphasis on those approved from 2013 to the present. Representative synthetic strategies are highlighted to illustrate the versatility of the indole framework in drug design. Furthermore, we systematically discuss each drug's pharmacology, mechanisms of action, and clinical applications. By integrating synthetic chemistry with clinical applications, this review aims to provide medicinal chemists and drug developers with guidance for leveraging indole scaffolds in next-generation therapeutic discovery and development.
Wu W, Yang S, Liu J
… +3 more, Wang Y, Pan D, Zhou Y
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41568436
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The PCSK9-LDLR interaction, driving elevated LDL-C, is a key driver of ASCVD pathogenesis. Identifying peptides disrupting this interaction offers an alternative ASCVD therapy. Herein, structure-based virtual screening...The PCSK9-LDLR interaction, driving elevated LDL-C, is a key driver of ASCVD pathogenesis. Identifying peptides disrupting this interaction offers an alternative ASCVD therapy. Herein, structure-based virtual screening with Pep2-8 as a control, we identified TPP-4, a high-affinity peptide inhibitor targeting PCSK9. Compared to Pep2-8, TPP-4 showed lower binding free energy (approximately -9.8 kcal/mol) and values ( = 0.08 ± 0.01 μM), interacting with PCSK9's LDLR-binding domain through multiple interactions. CD spectroscopy also provided indirect evidence for these key interactions. Additionally, it stably bound to the LDLR binding domain of PCSK9 during 100 ns MD simulations. It showed good serum stability, negligible HepG2 cytotoxicity, and restored surface LDLR (EC = 1.12 ± 0.05 μM). In mice, TPP-4 upregulated hepatic LDLR and reduced plasma total cholesterol levels. In conclusion, these data demonstrate that TPP-4 could be a high-affinity and potent candidate peptide for ASCVD treatment.
Ji YJ, Kang MH, Han SH
… +4 more, Lee YS, Kim MJ, Kim JH, Jang GY
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41568417
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is a widely used herb in Oriental medicine, known for its wide range of therapeutic applications. The present study was conducted with the aim of evaluating the effects of selected compounds isolated from , including 4-h...is a widely used herb in Oriental medicine, known for its wide range of therapeutic applications. The present study was conducted with the aim of evaluating the effects of selected compounds isolated from , including 4-hydroxyacetophenone (CW1), 2,4-dihydroxyacetophenone (CW2), K1N (CW3), and A (CW4), on the inflammatory response induced by treatment of macrophages with LPS. The study focused on the analysis of the MAPK and NF-κB pathways. The results showed that treatment with CW1, CW2, CW3 and CW4 inhibited the expression of p-ERK, p-JNK, p-p38 and p-IkBa in LPS-induced macrophages, with CW4 exhibiting the greatest inhibitory effects. Furthermore, CW4 treatment showed the most significant inhibitory effect on p-IκB-α/IκB-α expression in the NF-κB pathway. In conclusion, the data demonstrate that CW4 exerts a robust inhibitory effect on macrophage inflammatory signalling pathways in the LPS-induced inflammatory response.
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41566873
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Lung cancer, a globally prevalent fatal malignancy, remains a major therapeutic challenge. X-linked inhibitor of apoptosis protein (XIAP) is overexpressed in various cancers, driving uncontrolled proliferation, while its...Lung cancer, a globally prevalent fatal malignancy, remains a major therapeutic challenge. X-linked inhibitor of apoptosis protein (XIAP) is overexpressed in various cancers, driving uncontrolled proliferation, while its specific inhibition suppresses tumour growth. Through virtual screening, we identified five novel candidate peptides (Peptides 1-5) with picomolar-level inhibitory activity. Peptide-5 showed the highest binding affinity ( = 10.2 ± 0.5 pM), and FP assay indicated that Peptide-5 competitively binds the BIR3 domain of XIAP against caspase-9. Molecular dynamics simulations confirmed the structural stability of its complex with XIAP. Meanwhile, Peptide-5 showed good serum and metabolic stability, as well as favourable cellular permeability. Notably, Peptide-5 exhibited potent antiproliferative activity against various tumour cells with no obvious toxicity to normal cells. Peptide-5 potentially activates apoptotic signalling through modulating the Bcl-2/Bax mRNA expression. In summary, our study confirms that Peptide-5 is a highly potent and promising XIAP-targeted inhibitor for the treatment of cancer.
Tseng HJ, Wu YW, Chen YL
… +8 more, Lin TE, Fang-Chin YT, Wu YL, Sung TY, Yen SC, Hsieh JH, Hsu KC, Pan SL
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41566772
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TGF-β promotes progression and metastasis in later stages of tumour development, and inhibitors targeting TGF-β or its receptor have faced clinical limitations due to toxicity and poor selectivity. This study aimed to id...TGF-β promotes progression and metastasis in later stages of tumour development, and inhibitors targeting TGF-β or its receptor have faced clinical limitations due to toxicity and poor selectivity. This study aimed to identify novel TGFβR1 inhibitors by screening the ChemDiv database using a structure-based virtual screening approach. Among the top-ranked compounds, 3282-0487 showed the highest potency. Its analogues were further evaluated, leading to four potent TGFβR1 inhibitors with sub-micromolar IC values. Molecular docking confirmed favourable binding interactions, and structure-activity relationship analysis highlighted key structural features contributing to inhibitory activity. Among these, compound 3282-0486 demonstrated the lowest IC values against colorectal cancer cells, inducing apoptosis and dose-dependent anti-migration effects. Its efficacy was further supported by changes in downstream TGFβR1 signalling, including p-Smad2, EMT markers, and PARP1 cleavage. Additionally, compound 3282-0486 exhibited selectivity for TGFβR1. Overall, these findings support compound 3282-0486 as a promising TGFβR1 inhibitor with therapeutic potential.
Vo HVT, Patton GN, Park JS
… +3 more, Kim SJ, Kim N, Lee HJ
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41555543
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Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, are directly involved in the degradation of the extracellular matrix preceding uncontrolled cancer growth and metastasis. For these reasons, MMPs are consid...Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, are directly involved in the degradation of the extracellular matrix preceding uncontrolled cancer growth and metastasis. For these reasons, MMPs are considered key therapeutic targets in the development of cancer treatments. Acknowledged for its prophylactic effects against various diseases including cancer, physical exercise has been reported to boost the immune system, enhance endogenous defence mechanisms, manage oxidative stress, and regulate MMP. Despite its benefits, patients with compromised capacity for physical activity due to injuries and frailty are often unable to take advantage of them. As a possible solution for this problem, the alternative therapeutic approach of exercise mimetics has been gaining traction through pharmacological interventions. Exercise mimetics are pharmacological agents that partially mimic the molecular and physiological benefits of physical exercise without requiring actual physical activity. Recent studies have indicated that the potential of these compounds may serve as candidates for further investigation in cancer treatment. In this study, the possible anti-cancer and anti-metastatic-related effects of six selected exercise mimetics (., , , , , , and ) were investigated by targeting activity and/or expression of MMP-2/9 in model. These compounds (i) inhibited MMP-2 activity by interacting with the active site and/or allosteric sites, (ii) downregulated MMP-2/9 expression by influencing STAT3 signalling pathways, and (iii) reduced lung cancer cells (A549) viability to varying degrees. Among the exercise mimetics, Icariin and Berberine have relatively stronger effects on both the activity of MMP-2 and the expression of MMP-2/9 in cancer cells. These findings highlight the novel potential of exercise mimetics as targeted cancer therapeutics through the regulation of MMP activity and expression in cancer progression and metastasis.
Watanabe K, Tagami T, Biwa C
… +5 more, Kawasaki M, Adachi N, Moriya T, Senda T, Okuyama M
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41534875
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Maltase-glucoamylase (MGAM) is a small-intestinal enzyme comprising two tandem α-glucosidase units, NtMGAM and CtMGAM, each capable of hydrolysing maltodextrins into glucose. MGAM serves as a therapeutic target for manag...Maltase-glucoamylase (MGAM) is a small-intestinal enzyme comprising two tandem α-glucosidase units, NtMGAM and CtMGAM, each capable of hydrolysing maltodextrins into glucose. MGAM serves as a therapeutic target for managing postprandial hyperglycaemia; comprehensive insights into its full-length three-dimensional structure and inhibitor kinetics remains limited. Here, we demonstrate that the α-glucosidase in porcine serum is comparable to that encoded by the MGAM gene. Using cryo-electron microscopy, we determined the complex structure of serum MGAM with the inhibitor acarviosyl-maltotriose (AC5), which was found to bind exclusively to the active sites of each unit, confirming the presence of independent catalytic sites. AC5 was shown to exhibit mixed-type inhibition towards full-length serum MGAM and competitive inhibition against both recombinant NtMGAM and CtMGAM. The apparent mixed-type inhibition can be more accurately attributed to dual competitive inhibition mechanisms. These findings contribute to the advancement of functional foods and therapeutic interventions for postprandial hyperglycaemia and type 2 diabetes.
Liu P, Liu Y, Cheng L
… +6 more, Bao T, Li J, Wu J, Han J, Li T, Zhang D
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41534849
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The liver is essential for metabolism and detoxification and can regenerate effectively. However, severe injuries or major surgeries can hinder this ability, leading to liver insufficiency or failure. Recent research has...The liver is essential for metabolism and detoxification and can regenerate effectively. However, severe injuries or major surgeries can hinder this ability, leading to liver insufficiency or failure. Recent research has identified mitogen-activated protein kinase kinase 4 (MKK4) as a key negative regulator of liver regeneration, making it a promising therapeutic target. Inhibiting MKK4 reduces apoptosis and enhances liver regeneration, spurring interest in small molecule inhibitors of MKK4 for therapeutic strategies to promote liver recovery. This review systematically elucidates the structural characteristics and biological functions of MKK4, alongside its regulatory mechanisms in liver regeneration. It emphasises recent advancements in the research of small molecule inhibitors targeting MKK4 and offers a thorough and comprehensive analysis of the structure-activity relationships of the reported MKK4 inhibitors. The objective is to provide theoretical insights and research directions for the development of efficient and specific MKK4 inhibitors.
Zhao Y, Jia H, Wang Y
… +6 more, Sha S, An D, Yang S, Qian L, Ma Y, Xu L
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41507074
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The N-acetylglucosamine-1-phosphate transferase (WecA)is a potential target for developing anti-tuberculosis drugs, due to its critical role in the synthesis of mycobacterial cell wall. The enzymatic study of WecA and th...The N-acetylglucosamine-1-phosphate transferase (WecA)is a potential target for developing anti-tuberculosis drugs, due to its critical role in the synthesis of mycobacterial cell wall. The enzymatic study of WecA and the discovery of WecA inhibitors are therefore justified. However, WecA is a membrane protein with 11 transmembrane domains, making it difficult to be obtained, and even more difficult to perform activity studies. In order to gain sufficient WecA protein for activity investigation, the () Lemo21(DE3) strain was utilised in this study. The expression level of WecA was precisely regulated by T7 lysozyme. Purified WecA was obtained by affinity chromatography and identified by mass spectrometry. The kinetic properties of WecA were determined based on the detection of the product UMP. In addition, tunicamycin proved to be a competitive inhibitor. These results will lay theoretical foundations for the elucidation of WecA catalytic mechanism and the development of WecA inhibitors.
Wang Z, Feng J, Yi C
… +3 more, Zhang W, Fu X, Yu Y
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41504312
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Monoamine oxidase B (MAO-B) inhibitors may be an effective therapeutic approach for Parkinson's disease. This study designed and synthesised a series of N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalen-1-amine derivatives...Monoamine oxidase B (MAO-B) inhibitors may be an effective therapeutic approach for Parkinson's disease. This study designed and synthesised a series of N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalen-1-amine derivatives and evaluated their inhibitory activity against human MAO-B (hMAO-B). Most compounds exhibited inhibitory activity and selectivity, with compounds and demonstrating the strongest inhibitory potency (IC = 0.066 ± 0.03 μM and 0.070 ± 0.002 μM, respectively) and selectivity indices (SI > 151 and 134), which were superior to the positive control rasagiline. Enzyme kinetic studies confirmed that these representative active compounds exhibited mixed reversible inhibition of hMAO-B. Molecular docking and kinetic analyses indicated that compound binds stably to the hMAO-B active site. Concurrently, they exhibited low neurotoxicity and protective effects against 6-OHDA-induced damage in SH-SY5Y neuroblastoma cells. Therefore, we propose these active compounds as potential drug candidates for further investigation.
Fu R, Huang M, Liu T
… +3 more, Chen Y, Li X, Jiang W
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41495987
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We recently observed a significantly higher level of renalase (RNLS) in aldosterone-producing adenomas (APAs) than in the APA-adjacent adrenal glands (AAGs). RNLS is a flavin adenine dinucleotide-dependent monoamine oxid...We recently observed a significantly higher level of renalase (RNLS) in aldosterone-producing adenomas (APAs) than in the APA-adjacent adrenal glands (AAGs). RNLS is a flavin adenine dinucleotide-dependent monoamine oxidase. In this study, we investi-gated the effect of RNLS on adrenocortical aldosterone production. RNLS upregulated aldosterone production in adrenocortical cells without interfering with cell proliferation. RNLS (4 μg/ml) increased the mRNA expression of HSD3B2 ( = 0.0128) and CYP21A2 ( = 0.0013) and markedly stimulated that of CYP11B2 ( < 0.0001). Regarding the mechanism, we excluded classical calcium signalling stimulation and found that RNLS activated cAMP/PKA signalling and then upregulated the transcription factor NR4A2 and the phosphorylation of ATF/CREB family members. Immunofluorescence and immuno-precipitation results revealed that RNLS bound to the receptor PMCA4b on the cell membrane, with siPMCA4b preventing RNLS from exerting pro-aldosterone production ( = 0.0157, RNLS+siPMCA4b vs RNLS+siNC). RNLS facilitates aldosterone secretion and may emerge as a hazardous molecule for promoting aldosterone-mediated pathological conditions.
Knejzlík Z, Bulvas O, Dedola M
… +3 more, Štefek M, Nencka R, Pichová I
J Enzyme Inhib Med Chem
· 2026 Dec · PMID 41495879
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Inosine 5'-monophosphate dehydrogenase (IMPDH) is a promising antimicrobial target due to its central role in guanine nucleotide biosynthesis. Accurate and reliable kinetic measurements are essential for evaluating inhib...Inosine 5'-monophosphate dehydrogenase (IMPDH) is a promising antimicrobial target due to its central role in guanine nucleotide biosynthesis. Accurate and reliable kinetic measurements are essential for evaluating inhibitors. However, the enzyme's complex reaction mechanism and substrate cooperativity complicate analysis, leading to inconsistent reports on IMPDH reaction kinetics in key pathogenic mycobacteria. Here, we present an in-depth biochemical analysis of mycobacterial IMPDH, revealing pH-dependent cooperativity mediated by IMP-driven interactions between catalytic domains within the tetramer. This mechanism may result in paradoxical activation by IMP-competitive inhibitors under specific substrate conditions. We further show that such effects may influence apparent inhibition by the natural allosteric regulators GTP and ppGpp. Based on these findings, we outline practical recommendations for designing kinetic experiments that reflect physiologic conditions with the aim of more accurately evaluating IMPDH inhibitors for drug discovery.