RÉSUMÉ
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. Although drugs focusing on reducing amyloid ß slow progression, they fail to improve cognitive function. Deficits in glucose metabolism are reflected in FDG-PET and parallel the neurodegeneration and synaptic marker loss closely preceding cognitive decline, but the role of metabolic deficits as a cause or consequence of neurodegeneration is unclear. Pyruvate dehydrogenase (PDH) is lost in AD and an important enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle by converting pyruvate into acetyl-CoA. It is negatively regulated by pyruvate dehydrogenase kinase (PDHK) through phosphorylation. METHODS: In the present study, we assessed the in vitro/ in vivo pharmacological profile of the novel PDHK inhibitor that we discovered, Compound A. We also assessed the effects of Compound A on AD-related phenotypes including neuron loss and cognitive impairment using 5xFAD model mice. RESULTS: Compound A inhibited human PDHK1, 2 and 3 but had no inhibitory activity on PDHK4. In primary neurons, Compound A enhanced pyruvate and lactate utilization, but did not change glucose levels. In contrast, in primary astrocytes, Compound A enhanced pyruvate and glucose utilization and enhanced lactate production. In an efficacy study using 5xFAD mice, Compound A ameliorated the cognitive dysfunction in the novel object recognition test and Morris water maze. Moreover, Compound A prevented neuron loss in the hippocampus and cerebral cortex of 5xFAD without affecting amyloid ß deposits. CONCLUSIONS: These results suggest ameliorating metabolic deficits by activating PDH by Compound A can limit neurodegeneration and is a promising therapeutic strategy for treating AD.
Sujet(s)
Maladie d'Alzheimer , Dysfonctionnement cognitif , Modèles animaux de maladie humaine , Souris transgéniques , Animaux , Maladie d'Alzheimer/traitement médicamenteux , Maladie d'Alzheimer/métabolisme , Maladie d'Alzheimer/anatomopathologie , Dysfonctionnement cognitif/traitement médicamenteux , Dysfonctionnement cognitif/métabolisme , Humains , Souris , Pyruvate dehydrogenase acetyl-transferring kinase/antagonistes et inhibiteurs , Pyruvate dehydrogenase acetyl-transferring kinase/métabolisme , Peptides bêta-amyloïdes/métabolisme , Neurones/effets des médicaments et des substances chimiques , Neurones/métabolisme , Neurones/anatomopathologie , Protein-Serine-Threonine Kinases/antagonistes et inhibiteurs , Protein-Serine-Threonine Kinases/métabolisme , Mâle , Cellules cultivées , Antienzymes/pharmacologie , Antienzymes/usage thérapeutiqueRÉSUMÉ
Nitric oxide (NO) has been defined as the "miracle molecule" due to its essential pleiotropic role in living systems. Besides its implications in physiologic functions, it is also involved in the development of several disease states, and understanding this ambivalence is crucial for medicinal chemists to develop therapeutic strategies that regulate NO production without compromising its beneficial functions in cell physiology. Although nitric oxide synthase (NOS), i.e., the enzyme deputed to the NO biosynthesis, is a well-recognized druggable target to regulate NO bioavailability, some issues have emerged during the past decades, limiting the progress of NOS modulators in clinical trials. In the present review, we discuss the most promising advancements in the research of small molecules that are able to regulate NOS activity with improved pharmacodynamic and pharmacokinetic profiles, providing an updated framework of this research field that could be useful for the design and development of new NOS modulators.
Sujet(s)
Antienzymes , Nitric oxide synthase , Monoxyde d'azote , Humains , Nitric oxide synthase/métabolisme , Animaux , Monoxyde d'azote/métabolisme , Antienzymes/pharmacologie , Antienzymes/composition chimique , Antienzymes/usage thérapeutiqueRÉSUMÉ
The main uric acid-lowering agents in clinical use for hyperuricemia and gout are xanthine oxidase (XO) inhibitors or urate transporter 1 (URAT1) inhibitors. While these therapies can partially control the disease, they have various limitations. The development of XO/URAT1 dual inhibitors offers the potential to enhance therapeutic potency and reduce toxicity compared with single-target inhibitors. Through scaffold hopping from the XO inhibitor febuxostat (2) and the URAT1 inhibitor probenecid (3), followed by structure-activity relationship (SAR) studies, we identified compound 27 as a potent dual inhibitor of XO and URAT1. Compound 27 demonstrated significant dual inhibition in vitro (XO IC50 = 35 nM; URAT1 IC50 = 31 nM) and exhibited favorable pharmacology and pharmacokinetic (PK) profiles in multiple species including monkeys. Furthermore, toxicity studies in rats and monkeys revealed general safety profiles, supporting that compound 27 emerges as a promising novel drug candidate with potent XO/URAT1 dual inhibition for the treatment of gout.
Sujet(s)
Goutte , Hyperuricémie , Transporteurs d'anions organiques , Transporteurs de cations organiques , Xanthine oxidase , Xanthine oxidase/antagonistes et inhibiteurs , Xanthine oxidase/métabolisme , Hyperuricémie/traitement médicamenteux , Animaux , Goutte/traitement médicamenteux , Relation structure-activité , Humains , Transporteurs d'anions organiques/antagonistes et inhibiteurs , Transporteurs d'anions organiques/métabolisme , Rats , Transporteurs de cations organiques/antagonistes et inhibiteurs , Transporteurs de cations organiques/métabolisme , Administration par voie orale , Rat Sprague-Dawley , Mâle , Macaca fascicularis , Fébuxostat/pharmacologie , Fébuxostat/pharmacocinétique , Fébuxostat/usage thérapeutique , Fébuxostat/composition chimique , Découverte de médicament , Antienzymes/pharmacologie , Antienzymes/pharmacocinétique , Antienzymes/usage thérapeutique , Antienzymes/composition chimique , Antienzymes/synthèse chimique , Antigoutteux/pharmacocinétique , Antigoutteux/pharmacologie , Antigoutteux/usage thérapeutique , Antigoutteux/composition chimique , Antigoutteux/synthèse chimique , Biodisponibilité , Probénécide/pharmacologieRÉSUMÉ
Inhibiting O-GlcNAcase and thereby up-regulation of the O-GlcNAc levels of tau was a potential approach for discovering AD treatments. Herein, a series of novel highly potent OGA inhibitors embracing a 4-(arylethynyl)piperidine moiety was achieved by capitalizing on the substrate recognition domain. Extensive structure-activity relationships resulted in compound 81 with significant enzymatic inhibition (IC50 = 4.93 ± 2.05 nM) and cellular potency (EC50 = 7.47 ± 3.96 nM in PC12 cells). It markedly increased the protein O-GlcNAcylation levels and reduced the phosphorylation on Ser199, Thr205, and Ser396 of tau in the OA-injured SH-SY5Y cell model, suggesting its potential role for AD treatment. In fact, an in vivo efficacy of ameliorating cognitive impairment was observed following treatment of APP/PS1 mice with compound 81 (100 mg/kg). Additionally, the appropriate plasma PK and beneficial BBB penetration properties were also observed. Compound 81 deserves to be further explored as an anti-AD agent.
Sujet(s)
Maladie d'Alzheimer , Antienzymes , Pipéridines , beta-N-Acetylhexosaminidases , Maladie d'Alzheimer/traitement médicamenteux , Animaux , Pipéridines/pharmacologie , Pipéridines/usage thérapeutique , Pipéridines/synthèse chimique , Pipéridines/composition chimique , Pipéridines/pharmacocinétique , Humains , Relation structure-activité , beta-N-Acetylhexosaminidases/antagonistes et inhibiteurs , beta-N-Acetylhexosaminidases/métabolisme , Rats , Antienzymes/pharmacologie , Antienzymes/synthèse chimique , Antienzymes/composition chimique , Antienzymes/usage thérapeutique , Antienzymes/pharmacocinétique , Souris , Cellules PC12 , Découverte de médicament , Souris transgéniques , Protéines tau/métabolisme , Protéines tau/antagonistes et inhibiteurs , MâleRÉSUMÉ
As an oncogenic phosphatase, SHP2 acts as a converging node in the RTK-RAS-MAPK signaling pathway in cancer cells and suppresses antitumor immunity by passing signals downstream of PD-1. Here, we utilized the extra druggable pocket outside the previously identified SHP2 allosteric tunnel site by the (6,5 fused), 6 spirocyclic system. The optimized compound, JAB-3312, exhibited a SHP2 binding Kd of 0.37 nM, SHP2 enzymatic IC50 of 1.9 nM, KYSE-520 antiproliferative IC50 of 7.4 nM and p-ERK inhibitory IC50 of 0.23 nM. For JAB-3312, an oral dose of 1.0 mg/kg QD was sufficient to achieve 95% TGI in KYSE-520 xenograft model of mouse. JAB-3312 was well-tolerated in animal models, and a close correlation was observed between the plasma concentration of JAB-3312 and the p-ERK inhibition in tumors. Currently, JAB-3312 is undergoing clinical trials as a potential anticancer agent.
Sujet(s)
Antinéoplasiques , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , Humains , Animaux , Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonistes et inhibiteurs , Protein Tyrosine Phosphatase, Non-Receptor Type 11/métabolisme , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/pharmacocinétique , Antinéoplasiques/synthèse chimique , Souris , Régulation allostérique/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Relation structure-activité , Tests d'activité antitumorale sur modèle de xénogreffe , Prolifération cellulaire/effets des médicaments et des substances chimiques , Découverte de médicament , Antienzymes/pharmacologie , Antienzymes/composition chimique , Antienzymes/usage thérapeutique , Antienzymes/synthèse chimique , Antienzymes/pharmacocinétique , Souris nude , Femelle , Tumeurs/traitement médicamenteuxRÉSUMÉ
Gastric cancer is a remarkably heterogeneous tumor. Despite some advances in the diagnosis and treatment of gastric cancer in recent years, the precise treatment and curative outcomes remain unsatisfactory. Poor prognosis continues to pose a major challenge in gastric cancer. Therefore, it is imperative to identify effective targets to improve the treatment and prognosis of gastric cancer patients. It should be noted that glycosylation, a novel form of posttranslational modification, is a process capable of regulating protein function and influencing cellular activities. Currently, numerous studies have shown that glycosylation plays vital roles in the occurrence and progression of gastric cancer. As crucial enzymes that regulate glycan synthesis in glycosylation processes, glycosyltransferases are potential targets for treating GC. Hence, investigating the regulation of glycosyltransferases and the expression of associated proteins in gastric cancer cells is highly important. In this review, the related glycosyltransferases and their related signaling pathways in gastric cancer, as well as the existing inhibitors of glycosyltransferases, provide more possibilities for targeted therapies for gastric cancer.
Sujet(s)
Glycosyltransferase , Thérapie moléculaire ciblée , Tumeurs de l'estomac , Tumeurs de l'estomac/traitement médicamenteux , Tumeurs de l'estomac/enzymologie , Tumeurs de l'estomac/anatomopathologie , Humains , Glycosyltransferase/métabolisme , Glycosyltransferase/antagonistes et inhibiteurs , Animaux , Glycosylation , Transduction du signal , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/pharmacologie , Antienzymes/usage thérapeutique , Antienzymes/pharmacologieRÉSUMÉ
Urolithiasis, characterized by the formation of solid crystalline structures within the urinary tract, presents a significant global health burden with high recurrence rates and limited treatment efficacy. Recent research has identified various protein receptors and enzymes implicated in the pathogenesis of urolithiasis, offering potential targets for therapeutic intervention. Protein receptors such as the calcium-sensing receptor and vasopressin V2 receptor play crucial roles in regulating urinary calcium excretion and water reabsorption, respectively, influencing stone formation. Additionally, modulation of receptors like the angiotensin II receptor and aldosterone receptor can impact renal function and electrolyte balance, contributing to stone prevention. Furthermore, enzymes such as urease inhibitors and xanthine oxidase inhibitors offer targeted approaches to prevent the formation of specific stone types. This review discusses the potential of targeting these receptors and enzymes for the treatment of urolithiasis, exploring associated drugs and their mechanisms of action. Despite promising avenues for personalized and precision medicine approaches, challenges such as the need for robust clinical evidence and ensuring cost-effectiveness must be addressed for the translation of these interventions into clinical practice. By overcoming these challenges, receptor-targeted therapies and enzyme inhibitors hold promise for revolutionizing the management of urolithiasis and reducing its global burden.
Sujet(s)
Thérapie moléculaire ciblée , Médecine de précision , Urolithiase , Humains , Urolithiase/traitement médicamenteux , Urolithiase/métabolisme , Médecine de précision/méthodes , Animaux , Antienzymes/usage thérapeutique , Antienzymes/pharmacologie , Urease/antagonistes et inhibiteurs , Urease/métabolisme , Récepteurs-détecteurs du calcium/métabolisme , Récepteurs-détecteurs du calcium/antagonistes et inhibiteurs , Xanthine oxidase/antagonistes et inhibiteurs , Xanthine oxidase/métabolisme , Récepteurs à la vasopressine/métabolismeRÉSUMÉ
In the clinical development of farnesyltransferase inhibitors (FTIs) for HRAS-mutant tumors, responses varied by cancer type. Co-occurring mutations may affect responses. We aimed to uncover cooperative genetic events specific to HRAS-mutant tumors and to study their effect on sensitivity to FTIs. Using targeted sequencing data from the MSK-IMPACT and Dana-Farber Cancer Institute Genomic Evidence Neoplasia Information Exchange databases, we identified comutations that were observed predominantly in HRAS-mutant versus KRAS-mutant or NRAS-mutant cancers. HRAS-mutant cancers had a higher frequency of coaltered mutations (48.8%) in the MAPK, PI3K, or RTK pathway genes, compared with KRAS-mutant (41.4%) and NRAS-mutant (38.4%) cancers (p < 0.05). Class 3 BRAF, NF1, PTEN, and PIK3CA mutations were more prevalent in HRAS-mutant lineages. To study the effects of comutations on sensitivity to FTIs, HrasG13R was transfected into "RASless" (Kraslox/lox/Hras-/-/Nras-/-/RERTert/ert) mouse embryonic fibroblasts (MEFs), which sensitized nontransfected MEFs to tipifarnib. Comutation in the form of Pten or Nf1 deletion and Pik3caH1047R transduction led to resistance to tipifarnib in HrasG13R-transfected MEFs in the presence or absence of KrasWT, whereas BrafG466E transduction led to resistance to tipifarnib only in the presence of KrasWT. Combined treatment with tipifarnib and MEK inhibition sensitized cells to tipifarnib in all settings, including in MEFs with PI3K pathway comutations. HRAS-mutant tumors demonstrate lineage-dependent MAPK or PI3K pathway alterations, which confer resistance to tipifarnib. The combined use of FTIs and MEK inhibition is a promising strategy for HRAS-mutant tumors.
Sujet(s)
Résistance aux médicaments antinéoplasiques , Farnesyltranstransferase , Mutation , Protéines proto-oncogènes p21(ras) , Humains , Farnesyltranstransferase/antagonistes et inhibiteurs , Farnesyltranstransferase/génétique , Résistance aux médicaments antinéoplasiques/génétique , Protéines proto-oncogènes p21(ras)/génétique , Animaux , Antienzymes/pharmacologie , Antienzymes/usage thérapeutique , Tumeurs/génétique , Tumeurs/traitement médicamenteux , Tumeurs/anatomopathologie , Lignée cellulaire tumorale , Souris , Quinolinone/pharmacologie , Transduction du signal/effets des médicaments et des substances chimiques , Transduction du signal/génétique , Génomique/méthodesRÉSUMÉ
Inhibition of soluble epoxide hydrolase (sEH) is a promising therapeutic strategy for treating neuropathic pain. These inhibitors effectively reduce diabetic neuropathic pain and inflammation induced by Freund's adjuvant which makes them a suitable alternative to traditional opioids. This study showcased the notable analgesic effects of compound AMHDU (1,1'-(hexane-1,6-diyl)bis(3-((adamantan-1-yl)methyl)urea)) in both inflammatory and diabetic neuropathy models. While lacking anti-inflammatory properties in a paw edema model, AMHDU is comparable to celecoxib as an analgesic in 30 mg/kg dose administrated by intraperitoneal injection. In a diabetic tactile allodynia model, AMHDU showed a prominent analgesic activity in 10 mg/kg intraperitoneal dose (p < 0.05). The effect is comparable to that of gabapentin, but without the risk of dependence due to a different mechanism of action. Low acute oral toxicity (>2000 mg/kg) and a high therapeutic index makes AMHDU a promising candidate for further structure optimization and preclinical evaluation.
Sujet(s)
Analgésiques , Epoxide hydrolase , Névralgie , Epoxide hydrolase/antagonistes et inhibiteurs , Epoxide hydrolase/métabolisme , Animaux , Névralgie/traitement médicamenteux , Mâle , Souris , Analgésiques/pharmacologie , Analgésiques/usage thérapeutique , Hyperalgésie/traitement médicamenteux , Modèles animaux de maladie humaine , Antienzymes/pharmacologie , Antienzymes/usage thérapeutique , Neuropathies diabétiques/traitement médicamenteux , Urée/analogues et dérivés , Urée/pharmacologie , Évaluation préclinique de médicament , Oedème/traitement médicamenteux , Rats , Adamantane/analogues et dérivés , Adamantane/pharmacologie , Adamantane/usage thérapeutiqueRÉSUMÉ
Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amoebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used systemically. Here, we describe findings that demonstrate these agents are potent inhibitors of N. fowleri ENO (NfENO) and are lethal to amoebae. In particular, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX) was a potent enzyme inhibitor (IC50 = 0.14 ± 0.04 µM) that was toxic to trophozoites (EC50 = 0.21 ± 0.02 µM) while the reported CC50 was >300 µM. Molecular docking simulation revealed that HEX binds strongly to the active site of NfENO with a binding affinity of -8.6 kcal/mol. Metabolomic studies of parasites treated with HEX revealed a 4.5 to 78-fold accumulation of glycolytic intermediates upstream of NfENO. Last, nasal instillation of HEX increased longevity of amoebae-infected rodents. Two days after infection, animals were treated for 10 days with 3 mg/kg HEX, followed by one week of observation. At the end of the one-week observation, eight of 12 HEX-treated animals remained alive (resulting in an indeterminable median survival time) while one of 12 vehicle-treated rodents remained, yielding a median survival time of 10.9 days. However, intranasal HEX delivery was not curative as brains of six of the eight survivors were positive for amoebae. These findings suggest that HEX requires further evaluation to develop as a lead for treatment of PAM.
Sujet(s)
Protozooses du système nerveux central , Naegleria fowleri , Enolase , Animaux , Naegleria fowleri/effets des médicaments et des substances chimiques , Protozooses du système nerveux central/traitement médicamenteux , Protozooses du système nerveux central/parasitologie , Enolase/métabolisme , Enolase/antagonistes et inhibiteurs , Antienzymes/pharmacologie , Antienzymes/usage thérapeutique , Souris , Rats , Humains , Simulation de docking moléculaireRÉSUMÉ
Telomerase, crucial for maintaining telomere length, is an attractive target for cancer therapy due to its role in cellular immortality. Despite three decades of research efforts, no small-molecule telomerase inhibitors have been clinically approved, highlighting the extensive challenges in developing effective telomerase-based therapeutics. This review examines conventional and emerging methods to measure telomerase activity and discusses existing inhibitors, including oligonucleotides and small molecules. Furthermore, this review highlights recent breakthroughs in structural studies of telomerase using cryo-electron microscopy, which can facilitate improved structure-based drug design. Altogether, advancements in structural methodologies and high-throughput screening offer promising prospects for telomerase-based cancer therapeutic development.
Sujet(s)
Découverte de médicament , Antienzymes , Telomerase , Telomerase/antagonistes et inhibiteurs , Telomerase/métabolisme , Humains , Antienzymes/composition chimique , Antienzymes/pharmacologie , Antienzymes/usage thérapeutique , Découverte de médicament/méthodes , Cryomicroscopie électronique , Tumeurs/traitement médicamenteux , Conception de médicament , Télomère/métabolisme , Oligonucléotides/composition chimique , Antinéoplasiques/composition chimique , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutiqueRÉSUMÉ
Inhibiting diacylglycerol acetyltransferase (DGAT1, DGAT2) enzymes (iDGAT1, iDGAT2), involved in triglyceride (TG) synthesis, improves hepatic steatosis in metabolic dysfunction-associated steatotic liver disease (MASLD) patients. However, their potential synergism in disease onset (SLD) and progression (metabolic dysfunction-associated steatohepatitis, fibrosis) has been poorly explored. We investigated iDGAT1 and iDGAT2 efficacy, alone or combined (iDGAT1/2) on fat accumulation and hepatocellular injury in hepatocytes (HepG2) and on fibrogenic processes in hepatic stellate cells (LX2). We further tested whether the addition of MitoQ antioxidant to iDGAT1/2 would enhance their effects. SLD and MASH conditions were reproduced in vitro by supplementing Dulbecco's Modified Eagle's Medium (DMEM) with palmitic/oleic acids (PAOA) alone (SLD-medium), or plus Lipopolisaccaride (LPS), fructose, and glucose (MASH-medium). In SLD-medium, iDGAT1 and iDGAT2 individually, and even more in combination, reduced TG synthesis in HepG2 cells. Markers of hepatocellular damage were slightly decreased after single iDGAT exposure. Conversely, iDGAT1/2 counteracted ER/oxidative stress and inflammation and enhanced mitochondrial Tricarboxylic acid cycle (TCA) and respiration. In HepG2 cells under a MASH-like condition, only iDGAT1/2 effectively ameliorated TG content and oxidative and inflammatory mediators, further improving bioenergetic balance. LX2 cells, challenged with SLD/MASH media, showed less proliferation and slower migration rates in response to iDGAT1/2 drugs. MitoQ combined with iDGAT1/2 improved cell viability and dampened free fatty acid release by stimulating ß-oxidation. Dual DGAT inhibition combined with antioxidants open new perspectives for MASLD management.
Sujet(s)
Diacylglycerol O-acyltransferase , Triglycéride , Humains , Diacylglycerol O-acyltransferase/métabolisme , Diacylglycerol O-acyltransferase/antagonistes et inhibiteurs , Cellules HepG2 , Triglycéride/métabolisme , Antienzymes/pharmacologie , Antienzymes/usage thérapeutique , Cellules étoilées du foie/métabolisme , Cellules étoilées du foie/effets des médicaments et des substances chimiques , Stéatose hépatique/traitement médicamenteux , Stéatose hépatique/métabolisme , Stéatose hépatique/étiologie , Stress oxydatif/effets des médicaments et des substances chimiques , Antioxydants/pharmacologie , Hépatocytes/métabolisme , Hépatocytes/effets des médicaments et des substances chimiquesRÉSUMÉ
Hyperuricemia is with growing incidence and of high risk to develop into gout and other metabolic diseases. The key enzyme catalyzing uric acid synthesis, xanthine oxidoreductase (XOR) is a vital target for anti-hyperuricemic drugs, while XOR inhibitors characterized as both potent and safe are currently in urgent need. In this study, a novel small molecule compound, CC15009, was identified as a specific XOR inhibitor. CC15009 exerted strongest in vitro XOR inhibitory activity among current XOR inhibitors. It also showed favorable dose-dependent uric acid-lowering effects in two different XOR substrate-induced hyperuricemic mouse models, which was significantly superior than the current first-line drug, allopurinol. Mechanically, the direct binding of CC15009 against XOR was confirmed by molecular docking and SPR analysis. The inhibition mode was competitive and reversible. Besides, the potential antioxidant activity of CC15009 was indicated by its strong inhibitory activity against the oxidized isoform of XOR, which reduced ROS generation as the byproduct. Regarding the safety concerns of current XOR inhibitors, especially in cardiovascular risks, the safety of CC15009 was comprehensively evaluated. No significant abnormality was observed in the acute, subacute toxicity tests and mini-AMES test. Notably, there was no obvious inhibition of CC15009 against cardiac ion channels, including hERG, Nav1.5, Cav1.2 at the concentration of 30⯵M, indicating its lower cardiovascular risk. Taken together, our results supported CC15009 as a candidate of high efficacy and safety profile to treat hyperuricemia through direct XOR inhibition.
Sujet(s)
Antienzymes , Hyperuricémie , Acide urique , Xanthine dehydrogenase , Animaux , Humains , Mâle , Souris , Allopurinol/pharmacologie , Modèles animaux de maladie humaine , Relation dose-effet des médicaments , Antienzymes/pharmacologie , Antienzymes/composition chimique , Antienzymes/effets indésirables , Antienzymes/usage thérapeutique , Hyperuricémie/traitement médicamenteux , Souris de lignée C57BL , Simulation de docking moléculaire , Acide urique/sang , Xanthine dehydrogenase/antagonistes et inhibiteurs , Xanthine dehydrogenase/métabolismeRÉSUMÉ
DCN1, a critical co-E3 ligase in the neddylation process, mediates the activation of Cullin-RING Ligases (CRLs) by selectively catalyzing cullin neddylation, further regulating the activity of substrate proteins. It has been identified as an important target for human diseases, including cancers, fibrotic diseases, and cardiovascular disorders. This work aims to provide a perspective for the discovery of novel DCN1 inhibitors by the analysis of biological roles, protein structures, structure-activity relationships and design strategy disclosed in recent years. Additionally, we will discuss the current status, challenges and opportunities in hope of offering insights into the development of DCN1 inhibitors for human diseases.
Sujet(s)
Protéines et peptides de signalisation intracellulaire , Humains , Protéines et peptides de signalisation intracellulaire/métabolisme , Protéines et peptides de signalisation intracellulaire/antagonistes et inhibiteurs , Protéines et peptides de signalisation intracellulaire/composition chimique , Relation structure-activité , Animaux , Antienzymes/composition chimique , Antienzymes/usage thérapeutique , Antienzymes/pharmacologie , Tumeurs/traitement médicamenteux , Tumeurs/métabolismeRÉSUMÉ
Purpose: Intravitreal injection of anti-VEGF antibodies remains the primary therapy for exudative age-related macular degeneration (exAMD), although its efficacy is limited. Previous research has demonstrated that both a loss-of-function mutation of srr and the intravenous injection of a serine racemase inhibitor, L-aspartic acid ß-hydroxamate (L-ABH), significantly inhibit laser-induced choroidal neovascularization (CNV) in mice. Given that L-ABH is a small molecule, this study investigated the effects of L-ABH administered via eye drops on CNV, aiming to develop a noninvasive treatment strategy for exAMD. Methods: CNV models in mice and rhesus macaques were established through laser photocoagulation. Seven monkeys were randomly assigned to receive either saline solution or L-ABH eye drops. Intraperitoneal or intravenous injection of fluorescein characterized CNV in both mice and monkeys. Fluorescein fundus angiography was used to assess leakage, whereas optical coherence tomography measured retinal thickness in the monkeys. Results: L-ABH eye drops significantly reduced fluorescein leakage in laser-injured mice (P < 0.001 compared to saline). In laser-injured rhesus macaques, the average percent changes in leakage areas treated with L-ABH were 2.5% ± 25.8% (P = 0.004) and 1.5% ± 75.7% (P = 0.023 compared to saline solution) on day 14 and day 28, respectively. However, L-ABH eye drops did not significantly affect the number of grade IV laser spots or retinal thickness, whereas bevacizumab did. Conclusions: This study demonstrates the potential efficacy of an SRR inhibitor in two animal models of laser-induced CNV. Translational Relevance: This represents the first investigation into the effects of topical delivery of an SRR inhibitor on CNV.
Sujet(s)
Néovascularisation choroïdienne , Modèles animaux de maladie humaine , Angiographie fluorescéinique , Macaca mulatta , Souris de lignée C57BL , Tomographie par cohérence optique , Animaux , Néovascularisation choroïdienne/traitement médicamenteux , Néovascularisation choroïdienne/anatomopathologie , Souris , Racémases et épimérases/antagonistes et inhibiteurs , Racémases et épimérases/génétique , Racémases et épimérases/métabolisme , Coagulation par laser/effets indésirables , Solutions ophtalmiques , Mâle , Choroïde/effets des médicaments et des substances chimiques , Choroïde/anatomopathologie , Choroïde/imagerie diagnostique , Antienzymes/pharmacologie , Antienzymes/administration et posologie , Antienzymes/usage thérapeutique , Acides hydroxamiques/administration et posologie , Acides hydroxamiques/pharmacologie , Acides hydroxamiques/usage thérapeutiqueRÉSUMÉ
Overexpression of protein tyrosine phosphatase 1B (PTP1B) disrupts signaling pathways and results in numerous human diseases. In particular, its involvement has been well documented in the pathogenesis of metabolic disorders (diabetes mellitus type I and type II, fatty liver disease, and obesity); neurodegenerative diseases (Alzheimer's disease, Parkinson's disease); major depressive disorder; calcific aortic valve disease; as well as several cancer types. Given this multitude of therapeutic applications, shortly after identification of PTP1B and its role, the pursuit to introduce safe and selective enzyme inhibitors began. Regrettably, efforts undertaken so far have proved unsuccessful, since all proposed PTP1B inhibitors failed, or are yet to complete, clinical trials. Intending to aid introduction of the new generation of PTP1B inhibitors, this work collects and organizes the current state of the art. In particular, this review intends to elucidate intricate relations between numerous diseases associated with the overexpression of PTP1B, as we believe that it is of the utmost significance to establish and follow a brand-new holistic approach in the treatment of interconnected conditions. With this in mind, this comprehensive review aims to validate the PTP1B enzyme as a promising molecular target, and to reinforce future research in this direction.
Sujet(s)
Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Humains , Protein Tyrosine Phosphatase, Non-Receptor Type 1/métabolisme , Protein Tyrosine Phosphatase, Non-Receptor Type 1/génétique , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonistes et inhibiteurs , Tumeurs/métabolisme , Tumeurs/enzymologie , Tumeurs/génétique , Maladies neurodégénératives/métabolisme , Maladies neurodégénératives/enzymologie , Antienzymes/usage thérapeutique , Antienzymes/pharmacologie , Maladies métaboliques/métabolisme , Maladies métaboliques/enzymologie , Animaux , Transduction du signalRÉSUMÉ
Aldo-keto reductases (AKRs) are a superfamily of enzymes that play crucial roles in various cellular processes, including the metabolism of xenobiotics, steroids, and carbohydrates. A growing body of evidence has unveiled the involvement of AKRs in the development and progression of various cancers. AKRs are aberrantly expressed in a wide range of malignant tumors. Dysregulated expression of AKRs enables the acquisition of hallmark traits of cancer by activating oncogenic signaling pathways and contributing to chemoresistance. AKRs have emerged as promising oncotherapeutic targets given their pivotal role in cancer development and progression. Inhibition of aldose reductase (AR), either alone or in combination with chemotherapeutic drugs, has evolved as a pragmatic therapeutic option for cancer. Several classes of synthetic aldo-keto reductase (AKR) inhibitors have been developed as potential anticancer agents, some of which have shown promise in clinical trials. Many AKR inhibitors from natural sources also exhibit anticancer effects. Small molecule inhibitors targeting specific AKR isoforms have shown promise in preclinical studies. These inhibitors disrupt the activation of oncogenic signaling by modulating transcription factors and kinases and sensitizing cancer cells to chemotherapy. In this review, we discuss the physiological functions of human AKRs, the aberrant expression of AKRs in malignancies, the involvement of AKRs in the acquisition of cancer hallmarks, and the role of AKRs in oncogenic signaling, and drug resistance. Finally, the potential of aldose reductase inhibitors (ARIs) as anticancer drugs is summarized.
Sujet(s)
Aldo-keto reductases , Antinéoplasiques , Tumeurs , Humains , Tumeurs/traitement médicamenteux , Tumeurs/enzymologie , Tumeurs/anatomopathologie , Aldo-keto reductases/métabolisme , Aldo-keto reductases/génétique , Aldo-keto reductases/antagonistes et inhibiteurs , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/pharmacologie , Animaux , Antienzymes/usage thérapeutique , Antienzymes/pharmacologie , Médecine de précision , Transduction du signal , Aldose reductase/antagonistes et inhibiteurs , Aldose reductase/métabolismeRÉSUMÉ
This study presents a new approach for identifying myeloperoxidase (MPO) inhibitors with strong in vivo efficacy. By combining inhibitor-like rules and structure-based virtual screening, the pipeline achieved a 70% success rate in discovering diverse, nanomolar-potency reversible inhibitors and hypochlorous acid (HOCl) scavengers. Mechanistic analysis identified RL6 as a genuine MPO inhibitor and RL7 as a potent HOCl scavenger. Both compounds effectively suppressed HOCl production in cells and neutrophils, with RL6 showing a superior inhibition of neutrophil extracellular trap release (NETosis). In a gout arthritis mouse model, intraperitoneal RL6 administration reduced edema, peroxidase activity, and IL-1ß levels. RL6 also exhibited oral bioavailability, significantly reducing paw edema when administered orally. This study highlights the efficacy of integrating diverse screening methods to enhance virtual screening success, validating the anti-inflammatory potential of potent inhibitors, and advancing the MPO inhibitor research.
Sujet(s)
Goutte articulaire , Myeloperoxidase , Animaux , Myeloperoxidase/antagonistes et inhibiteurs , Myeloperoxidase/métabolisme , Goutte articulaire/traitement médicamenteux , Souris , Humains , Antienzymes/pharmacologie , Antienzymes/composition chimique , Antienzymes/usage thérapeutique , Mâle , Acide hypochloreux , Granulocytes neutrophiles/effets des médicaments et des substances chimiques , Granulocytes neutrophiles/métabolisme , Relation structure-activité , Évaluation préclinique de médicamentRÉSUMÉ
LSD1 has become an appealing target for the development of new pharmacologic agents to treat cardiovascular diseases, including heart failure. Herein, we reported the design, synthesis, and structure-activity relationship of a series of TCP-based derivatives targeting LSD1. Docking studies were employed to successfully elucidate the SAR. Particularly, compound 7d, characterized by low toxicity, demonstrated a high affinity for LSD1 at molecular and cellular levels. It also displayed favorable pharmacokinetic properties for oral dosing (e.g., F = 77.61%), effectively alleviating Ang II-induced NRCFs activation in vitro and reducing pathological myocardial remodeling in TAC-induced cardiac remodeling and heart failure in vivo. Additionally, mechanism studies revealed that suppression of myocardial dysfunction by compound 7d is related to LSD1 inhibition-induced TGFß signaling pathway repressing. In summary, the current report presents compound 7d as a potent LSD1 inhibitor with the potential for further development as a therapeutic agent for pressure overload-related heart failure.
Sujet(s)
Conception de médicament , Défaillance cardiaque , Histone Demethylases , Simulation de docking moléculaire , Histone Demethylases/antagonistes et inhibiteurs , Histone Demethylases/métabolisme , Défaillance cardiaque/traitement médicamenteux , Animaux , Relation structure-activité , Humains , Administration par voie orale , Antienzymes/pharmacologie , Antienzymes/synthèse chimique , Antienzymes/pharmacocinétique , Antienzymes/usage thérapeutique , Antienzymes/composition chimique , Antienzymes/administration et posologie , Mâle , Souris , Rats , Souris de lignée C57BLRÉSUMÉ
Increasing evidence has demonstrated that oxidative phosphorylation (OXPHOS) is closely associated with the progression of pancreatic cancer (PC). Given its central role in mitochondrial transcription, the human mitochondrial RNA polymerase (POLRMT) is a promising target for developing PC treatments. Herein, structure-activity relationship exploration led to the identification of compound S7, which was the first reported POLRMT inhibitor possessing single-digit nanomolar potency of inhibiting PC cells proliferation. Mechanistic studies showed that compound S7 exerted antiproliferative effects without affecting the cell cycle, apoptosis, mitochondrial membrane potential (MMP), or intracellular reactive oxygen species (ROS) levels specifically in MIA PaCa-2 cells. Notably, compound S7 inhibited tumor growth in MIA PaCa-2 xenograft tumor model with a tumor growth inhibition (TGI) rate of 64.52% demonstrating significant improvement compared to the positive control (44.80%). In conclusion, this work enriched SARs of POLRMT inhibitors, and compound S7 deserved further investigations of drug-likeness as a candidate for PC treatment.