Sesamolin serves as an MYH14 inhibitor to sensitize endometrial cancer to chemotherapy and endocrine therapy via suppressing MYH9/GSK3β/β-catenin signaling

Cellular & Molecular Biology Letters, Год журнала: 2024, Номер 29(1)

Опубликована: Май 2, 2024

Abstract Background Endometrial cancer (EC) is one of the most common gynecological cancers. Herein, we aimed to define role specific myosin family members in EC because this protein involved progression various Methods Bioinformatics analyses were performed reveal patients’ prognosis-associated genes patients with EC. Furthermore, colony formation, immunofluorescence, cell counting kit 8, wound healing, and transwell assays as well coimmunoprecipitation, cycloheximide chase, luciferase reporter, cellular thermal shift functionally mechanistically analyze human samples, lines, a mouse model, respectively. Results Machine learning techniques identified MYH14, member family, gene bioinformatics based on public databases showed that MYH14 was associated chemoresistance. Moreover, immunohistochemistry validated upregulation cases compared normal controls confirmed an independent unfavorable prognostic indicator impaired sensitivity carboplatin, paclitaxel, progesterone, increased proliferation metastasis The mechanistic study interacted MYH9 GSK3β-mediated β-catenin ubiquitination degradation, thus facilitating Wnt/β-catenin signaling pathway epithelial–mesenchymal transition. Sesamolin, natural compound extracted from Sesamum indicum (L.), directly targeted attenuated progression. Additionally, disrupted interplay between repressed MYH9-regulated signaling. vivo further verified sesamolin therapeutic drug without side effects. Conclusions independently responsible for poor overall survival time patients, it augmented by activating Targeting sesamolin, cytotoxicity-based approach, can be applied synergistically chemotherapy endocrine therapy eventually mitigate development. This emphasizes potential target valuable therapy. Graphical

Язык: Английский

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Coupling of surface plasmon resonance and mass spectrometry for molecular interaction studies in drug discovery

Drug Discovery Today, Год журнала: 2024, Номер 29(7), С. 104027 - 104027

Опубликована: Май 17, 2024

Various analytical technologies have been developed for the study of target-ligand interactions. The combination these gives pivotal information on binding mechanism, kinetics, affinity, residence time, and changes in molecular structures. Mass spectrometry (MS) offers structural information, enabling identification quantification Surface plasmon resonance (SPR) provides kinetic interaction real time. coupling MS SPR complements each other studies Over last two decades, capabilities added values SPR-MS reported. This review summarizes highlights benefits, applications, potential further research approach.

Язык: Английский

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The rise of NMR-integrated fragment-based drug discovery in China

Magnetic Resonance Letters, Год журнала: 2025, Номер unknown, С. 200179 - 200179

Опубликована: Янв. 1, 2025

Язык: Английский

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Evaluation of the Recent Dynamics for Funding Medicinal Chemistry Projects in Academia. Results of a Survey Conducted by IUPAC Division VII (Chemistry and Human Health)

Journal of Medicinal Chemistry, Год журнала: 2025, Номер 68(3), С. 2095 - 2104

Опубликована: Янв. 29, 2025

Data collected from scholars across twenty-three countries over the past decade (2010-2019) reveals a 40% decrease in financial support for medicinal chemistry projects. The decline is especially notable among projects focused on small organic molecules. This drop grants indicates troubling trend that could jeopardize future drug development by undermining research this crucial field. reduction funding not only affects ongoing but also threatens education and training of chemists, potentially leading to shortage skilled professionals pharmaceutical industry. To counteract negative trend, it imperative agencies, sector, government bodies take immediate action. Strengthening essential sustain innovation ensure continued advancement as vital academic practical discipline.

Язык: Английский

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Drugging Challenging Cancer Targets Using Fragment-Based Methods

Chemical Reviews, Год журнала: 2025, Номер unknown

Опубликована: Март 5, 2025

There are many highly validated cancer targets that difficult or impossible to drug due the absence of suitable pockets can bind small molecules. Fragment-based methods have been shown be a useful approach for identifying ligands proteins were previously thought undruggable. In this review, I will give an overview fragment-based ligand discovery and provide examples from our own work on how used discover high affinity challenging targets.

Язык: Английский

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Effect of precursors on carbon dot functionalization and applications: a review

The Analyst, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Carbon dots (CDs) are a type of carbon-based nanoparticle (NP) that have risen in popularity due to their unique tuneable physicochemical and optical properties.

Язык: Английский

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A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Май 6, 2025

Abstract Fis1-mediated mitochondrial localization of Drp1 and excessive fission occur in human pathologies associated with oxidative stress. However, it is not known how Fis1 detects stress what structural changes enable recruitment Drp1. We find that conformational change involving α1 helix exposes its only cysteine, Cys41. In the presence stress, exposed Cys41 activated forms a disulfide bridge covalent homodimers cause increased through to mitochondria. Our discovery small molecule, SP11, binds by engaging Cys41, data from genetically engineered cell lines lacking strongly suggest role homodimerization mitochondria fission. The structure Fis1-SP11 complex further confirms these insights related being sensor for Importantly, SP11 preserves integrity function cells during thus may serve as candidate molecule development treatment diseases underlying fragmentation dysfunction.

Язык: Английский

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Computer-Aided Drug Discovery for Undruggable Targets

Chemical Reviews, Год журнала: 2025, Номер unknown

Опубликована: Май 27, 2025

Undruggable targets are those of therapeutical significance but challenging for conventional drug design approaches. Such often exhibit unique features, including highly dynamic structures, a lack well-defined ligand-binding pockets, the presence conserved active sites, and functional modulation by protein-protein interactions. Recent advances in computational simulations artificial intelligence have revolutionized landscape, giving rise to innovative strategies overcoming these obstacles. In this review, we highlight latest progress approaches against undruggable targets, present several successful case studies, discuss remaining challenges future directions. Special emphasis is placed on four primary target categories: intrinsically disordered proteins, protein allosteric regulation, interactions, degradation, along with discussion emerging types. We also examine how AI-driven methodologies transformed field, from applications protein-ligand complex structure prediction virtual screening de novo ligand generation targets. Integration methods experimental techniques expected bring further breakthroughs overcome hurdles As field continues evolve, advancements hold great promise expand druggable space, offering new therapeutic opportunities previously untreatable diseases.

Язык: Английский

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Overcoming Clusterin-Induced Chemoresistance in Cancer: A Computational Study Using a Fragment-Based Drug Discovery Approach

Biology, Год журнала: 2025, Номер 14(6), С. 639 - 639

Опубликована: Май 30, 2025

Clusterin is one of the many known proteins implicated in cancer chemoresistance, which hinders effectiveness chemotherapy. This study aimed to design novel inhibitors targeting clusterin using fragment-based drug discovery (FBDD). approach aims develop new medicines by identifying small, simple molecules as “fragments” that can bind a specific target, such disease-causing protein. In this study, primary ligand-binding site and an allosteric on molecule were identified through hotspot analysis. We screened commercially available fragment libraries for anti-cancer activity applied “rule three” ensure drug-like properties. The highest-affinity underwent “fragment-growing” potential candidates. After docking toxicity screening, 194 candidate drugs identified. Quantitative structure-activity relationship (QSAR) analysis revealed chemical size complexity fragments significantly contributed their binding affinity. Pharmacokinetic analyses from FBDD followed molecular dynamics simulation top 1 final precursor demonstrated comparatively better affinity (average = −34.01 kcal/mol) than reference compound −6.15 significant ligand flexibility. offers strategy identify or may serve against clusterin-related chemoresistance.

Язык: Английский

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Synthesis and Herbicidal Activity of 2-(2-Oxo-3-pyridyl-benzothiazol-6-yloxy)hexanoic Acids

Journal of Agricultural and Food Chemistry, Год журнала: 2024, Номер 72(13), С. 7457 - 7463

Опубликована: Март 25, 2024

The discovery of a lead compound is fundamental to herbicide innovation, but the limited availability valuable compounds has hindered their development in recent years. By utilizing structural diversity-oriented inactive group strategy, 3-(2-pyridyl)-benzothiazol-2-one was identified as promising scaffold for herbicides, starting from benzothiazole which an moiety commonly found herbicides such mefenacet, benazolin, benzthiazuron, and fenthiaprop-ethyl. To investigate structure–activity relationship (SAR) these chemicals, series 2-(2-oxo-3-pyridyl-benzothiazol-6-yloxy)hexanoic acid derivatives (VI01 ∼ VI28) were synthesized through classical nucleophilic SNAr reaction using halogenated pyridines 6-methoxybenzothiazole-2-one. chemical structures all title confirmed by NMR MS analysis. Petri dish assays indicated that many exhibited potent herbicidal activity against both broad-leaf weeds grass at 1.0 mg/L. SAR analysis revealed presence trifluoromethyl 5-position pyridine essential activity. Furthermore, carboxylic esters exhibit higher compared amides free acids, decreased with extension carbon chain. postemergence VI03 16 species tested pot experiments greenhouse. demonstrated comparable efficacy controlling broadleaf superior carfentrazone ethyl. present study unveiled novel molecular exhibiting remarkably These findings are anticipated provide insights advancement new offer alternative approach managing resistant weeds.

Язык: Английский

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