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Cordycepin and Its Structural Derivatives Effectively Suppress the High Expression of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase in Breast Carcinomas: A Computational Drug Development Approach. 虫草素及其结构衍生物有效抑制乳腺癌中表皮生长因子受体酪氨酸激酶的高表达:一种计算药物开发方法。
IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-14 DOI: 10.2174/0109298673333884241119063458
Shabana Bibi, Partha Biswas, Md Mohaimenul Islam Tareq, Md Imtiaz, Md Hasan Jafre Shovon, Md Ridoy Hossain, Nasim Ahmed, Norah A Albekairi, Abdulrahman Alshammari, Md Nazmul Hasan

Background: Breast cancer is a frequently diagnosed malignant disease and the primary cause of mortality among women with cancer worldwide. The therapy options are influenced by the molecular subtype due to the intricate nature of the condition, which consists of various subtypes. By focusing on the activation of receptors, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase can be utilized as an effective drug target for therapeutic purposes of breast cancer.

Objectives: The objective of this study is to compare the underlying pharmacological properties of several modified agents to the parental Cordycepin to target and inhibit the EGFR tyrosine kinase high expression, and to discover the inhibitor with the highest affinity for this drug target to treat the breast cancer patients.

Methods: The Maestro Application of Schrödinger Suite Paid Software was initially employed for conducting extra precision (XP) structure-based virtual screening to evaluate the binding affinity of the Cordycepin and its 500 structural derivatives with the EGFR tyrosine kinase protein structure. In addition, the anti-breast cancer activity of the chosen compounds was assessed by looking at their drug-likeness and ADMET characteristics using Lipinski's rule of five along with Quantitative structure- activity relationship (QSAR) validation, the prediction of cell line anti-cancer, as well as anti- breast cancer activity of top docked scored compounds. Subsequently, the Desmond paid software- based molecular dynamics simulations (MDS) were conducted for a duration of 100 nanoseconds on the promising candidates followed by the binding free energy estimation was performed utilizing MM-GBSA analysis. To determine the stability of the protein-ligand complex, root-meansquare deviation (RMSD), root-mean-square fluctuation (RMSF), protein-ligand interactions, and other necessary parameters were evaluated from the 100 ns MDS Trajectory.

Results: Based on the overall analysis of our study, N (6)-octylamine adenosine (CID-194932) reported the optimum inhibitory potential against the EGFR tyrosine kinase protein, followed by Adenosine 5-monophosphate (CID-83862) and Cordycepin (CID-6303), which compared favorably to the control drug Vandetanib (CID-3081361).

Conclusion: Consequently, these derivative compounds Cordycepin have the potential to be utilized as lead molecules in the development of highly effective and potent EGFR tyrosine kinase inhibitors for the treatment of breast cancer patients.

背景:乳腺癌是一种常见的恶性疾病,也是全世界女性癌症患者死亡的主要原因。治疗方案受到分子亚型的影响,因为病情的复杂性,它由各种亚型组成。通过关注受体的激活,表皮生长因子受体酪氨酸激酶可以作为治疗乳腺癌的有效药物靶点。目的:本研究的目的是比较几种修饰药物与亲本虫草素靶向和抑制EGFR酪氨酸激酶高表达的潜在药理学性质,并发现对该药物靶点亲和力最高的抑制剂来治疗乳腺癌患者。方法:初步采用Schrödinger Suite付费软件Maestro Application进行基于extra precision (XP)结构的虚拟筛选,评价虫草素及其500个结构衍生物与EGFR酪氨酸激酶蛋白结构的结合亲和力。此外,采用Lipinski的五法则,通过药物相似性和ADMET特征,定量构效关系(QSAR)验证,细胞系抗癌预测以及得分最高的化合物的抗乳腺癌活性来评估所选化合物的抗乳腺癌活性。随后,利用Desmond软件对候选分子进行了持续100纳秒的分子动力学模拟(MDS),并利用MM-GBSA分析进行了结合自由能估算。为了确定蛋白质-配体复合物的稳定性,从100 ns MDS轨迹中评估了均方根偏差(RMSD)、均方根波动(RMSF)、蛋白质-配体相互作用和其他必要参数。结果:综合本研究结果,N(6)-辛胺腺苷(CID-194932)对EGFR酪氨酸激酶蛋白的抑制潜力最佳,其次为5-单磷酸腺苷(CID-83862)和虫草素(CID-6303),且优于对照药万德替尼(CID-3081361)。结论:虫草素衍生物有潜力作为先导分子开发高效的EGFR酪氨酸激酶抑制剂,用于治疗乳腺癌患者。
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引用次数: 0
Poly Lactic Co-glycolic Acid d-α-tocopheryl Polyethylene Glycol 1000 Succinate Fabricated Polyethylene Glycol Hybrid Nanoparticles of Imatinib Mesylate for the Treatment of Glioblastoma Multiforme. 聚乳酸共乙醇酸d-α-生育酚聚乙二醇1000琥珀酸制备甲磺酸伊马替尼聚乙二醇杂化纳米颗粒治疗多形胶质母细胞瘤。
IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-14 DOI: 10.2174/0109298673323270241118103546
Sankha Bhattacharya, Prafull Shinde, Amit Page, Bhupendra G Prajapati
<p><strong>Aims: </strong>This study aimed to develop Imatinib Mesylate (IMT)-loaded Poly Lactic-co-Glycolic Acid (PLGA)-D-α-tocopheryl polyethylene glycol succinate (TPGS)- Polyethylene glycol (PEG) hybrid nanoparticles (CSLHNPs) with optimized physicochemical properties for targeted delivery to glioblastoma multiforme.</p><p><strong>Background: </strong>Glioblastoma multiforme (GBM) is the most destructive type of brain tumor with several complications. Currently, most treatments for drug delivery for this disease face challenges due to the poor blood-brain barrier (BBB) and lack of site-specific delivery. Imatinib Mesylate (IMT) is one of the most effective drugs for GBM, but its primary issue is low bioavailability. Therefore, nanotechnology presents a promising solution for targeted IMT delivery to GBM. This article primarily explores the fabrication of IMT-loaded core-shell lipid-polymer hybrid nanoparticles (CSLHNPs) to achieve enhanced brain delivery with therapeutic efficacy.</p><p><strong>Objective: </strong>The primary objective of this study is to develop optimized, stable IMT-loaded hybrid nanoparticles with an encapsulated polymer matrix and to evaluate these nanoparticles using sophisticated instruments such as SEM and TEM to achieve smooth, spherical nanoparticles in a monodispersed phase.</p><p><strong>Method: </strong>The enhanced stable formulation yielded a notable increase in entrapment efficiency, reaching 58.89 ± 0.5%. The physical stability analysis of nanoparticles was assessed over 30 days under conditions of 25 ± 2°C and 60 ± 5% relative humidity. Hemolytic assays affirmed the biocompatibility and safety profile of the nanoparticles. in vitro drug release kinetics revealed a sustained IMT release over 48 hours.</p><p><strong>Results: </strong>The formulated CSLHNPs achieved a narrow size distribution with a mean vesicle diameter of 155.03 ± 2.41 nm and a low polydispersity index (PDI) of 0.23 ± 0.4, indicating monodispersity. A high negative zeta potential of -23.89 ± 3.47 mV ensured excellent colloidal stability in physiological conditions. XRD analysis confirmed the successful encapsulation of IMT within the nanoparticle matrix, with the drug transitioning to an amorphous state for enhanced dissolution. During Cell-Cell viability assays on LN229, glioblastoma cells were treated with IMT-loaded nanoparticles and showed a significantly enhanced inhibitory effect compared to free IMT. These hybrid nanoparticles demonstrated potential in reducing oxidative stress-induced cellular damage by mitigating reactive oxygen species (ROS). Thus, the prepared IMT hybrid nanoparticles showed higher cellular uptake and superior cytotoxicity compared to the plain drug.</p><p><strong>Conclusion: </strong>This study posits the IMT-PLGA-TPGS-DSPE PEG 2000-CSPLHNPs as a formidable and innovative drug delivery system for Glioblastoma Multiforme (GBM) treatment, warranting further exploration into their clinical application potential. Futur
目的:本研究旨在开发负载甲磺酸伊马替尼(IMT)的聚乳酸-羟基乙酸(PLGA)- d -α-生育酚基聚乙二醇丁二酸酯(TPGS)-聚乙二醇(PEG)混合纳米颗粒(CSLHNPs),该纳米颗粒具有优化的物理化学性质,可用于靶向递送多形性胶质母细胞瘤。背景:多形性胶质母细胞瘤(GBM)是最具破坏性的脑肿瘤类型,有多种并发症。目前,由于血脑屏障(BBB)差和缺乏部位特异性给药,大多数治疗这种疾病的药物递送面临挑战。甲磺酸伊马替尼(IMT)是治疗GBM最有效的药物之一,但其主要问题是生物利用度低。因此,纳米技术为靶向IMT递送GBM提供了一个很有前途的解决方案。本文主要探讨了负载imt的核-壳-脂质-聚合物混合纳米颗粒(CSLHNPs)的制备,以实现具有治疗效果的增强脑递送。目的:本研究的主要目的是开发具有封装聚合物基质的优化、稳定的负载imt的混合纳米粒子,并使用复杂的仪器(如扫描电镜和透射电镜)对这些纳米粒子进行评估,以获得单分散相中光滑的球形纳米粒子。方法:经强化稳定配方后,包封效率显著提高,达58.89±0.5%。在25±2°C和60±5%相对湿度条件下,对纳米颗粒进行30天的物理稳定性分析。溶血试验证实了纳米颗粒的生物相容性和安全性。体外药物释放动力学显示IMT在48小时内持续释放。结果:制备的CSLHNPs粒径分布较窄,平均囊泡直径为155.03±2.41 nm,多分散性指数(PDI)较低,为0.23±0.4,具有单分散性。-23.89±3.47 mV的高负zeta电位确保了生理条件下良好的胶体稳定性。XRD分析证实了IMT在纳米颗粒基质内的成功包封,药物转变为无定形状态以增强溶解。在LN229的细胞活力测试中,装载了IMT的纳米颗粒处理胶质母细胞瘤细胞,与游离IMT相比,显示出显著增强的抑制作用。这些混合纳米颗粒通过减少活性氧(ROS),显示出减少氧化应激诱导的细胞损伤的潜力。因此,与普通药物相比,制备的IMT杂交纳米颗粒具有更高的细胞摄取和优越的细胞毒性。结论:本研究认为IMT-PLGA-TPGS-DSPE PEG 2000-CSPLHNPs是治疗多形性胶质母细胞瘤(GBM)的一种强大的创新药物传递系统,值得进一步探索其临床应用潜力。未来的工作可能包括进行体内研究,以评估IMT-PLGA-TPGS-DSPE PEG 2000-CSPLHNPs在多形性胶质母细胞瘤(GBM)动物模型中的药代动力学、生物分布和治疗效果。此外,进一步的研究可能集中在优化纳米颗粒配方以增强靶向能力,研究不同储存条件下的长期稳定性,探索与纳米颗粒协同作用的潜在联合疗法,以及评估开发的药物传递系统的可扩展性和可制造性,以实现潜在的临床转化。整合先进的成像技术,实时跟踪和可视化肿瘤内的纳米颗粒分布,也可能是未来研究的一个有希望的方向。
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引用次数: 0
Current Perspectives of Diabetic Dyslipidemia and Treatment Modalities. 糖尿病性血脂异常的研究现状及治疗方法。
IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-13 DOI: 10.2174/0109298673336501241001093417
Gamze Akkus

Introduction: Diabetes mellitus is associated with an increased risk of atherosclerosis related to dyslipidemia. Although the terms hyperlipidemia and Diabetes Mellitus [DM] or diabetic dyslipidemia are interrelated to each other, these two conditions have some differences.

Aim: This study aimed to highlight possible mechanisms of hyperlipidemia and/or dyslipidemia in diabetic patients, which can be treated with available and newer hypolipidemic drugs. We also re-checked current specific guidelines and their recommendations on the management of patients with diabetic dyslipidemia.

Method: Comprehensive search of peer-reviewed journals was performed based on a wide range of keywords, including diabetes mellitus, dyslipidemia, hyperlipidemia, insulin resistance, free-fatty acids, cardiovascular disease, SCORE-2 calculation, statins, PCSK-9 inhibitors, and fibrates.

Discussion: Diabetic patients with dyslipidemia, including decreased HDL cholesterol, a predominance of small dense LDL particles, and increased triglyceride levels, are more prone to suffering from micro and macrovascular complications regardless of plasma fasting glucose levels. Recent guidelines suggested using the validated scoring system called SCORE2-Diabetes. Moderate to high dosages of statins, aiming for LDL cholesterol reduction, is still the cornerstone in the management of diabetic patients with dyslipidemia. Nowadays, other recommended non-statin drugs, including proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors or other novel therapeutic agents [bempedoic acid, inclisiran], are particularly important and given place in recently published guidelines.

Conclusion: The risk of developing atherosclerotic cardiovascular diseases in people with DM is relatively higher than in patients' without DM. Optimal management of lipid parameters and achieving desired target values in lipid parameters are still a challenging issue for clinicians.

导读:糖尿病与血脂异常相关的动脉粥样硬化风险增加相关。虽然高脂血症和糖尿病(DM)或糖尿病性血脂异常是相互关联的,但这两种情况也有一些区别。目的:本研究旨在揭示糖尿病患者高脂血症和/或血脂异常的可能机制,并可通过现有的和较新的降血脂药物进行治疗。我们还重新检查了当前的特定指南及其对糖尿病性血脂异常患者管理的建议。方法:根据糖尿病、血脂异常、高脂血症、胰岛素抵抗、游离脂肪酸、心血管疾病、SCORE-2计算、他汀类药物、PCSK-9抑制剂、贝特类药物等广泛的关键词,对同行评审期刊进行综合检索。讨论:无论空腹血糖水平如何,伴有血脂异常的糖尿病患者更容易出现微血管和大血管并发症,包括HDL胆固醇降低,小密度LDL颗粒占优势,甘油三酯水平升高。最近的指南建议使用经过验证的评分系统SCORE2-Diabetes。以降低低密度脂蛋白胆固醇为目标的中至高剂量他汀类药物仍然是糖尿病合并血脂异常患者管理的基石。如今,其他推荐的非他汀类药物,包括蛋白转化酶枯草杆菌素/kexin 9型[PCSK9]抑制剂或其他新型治疗药物[苯戊酸,inclisiran],在最近出版的指南中尤为重要。结论:糖尿病患者发生动脉粥样硬化性心血管疾病的风险相对高于非糖尿病患者。脂质参数的优化管理和脂质参数的理想目标值仍然是临床医生面临的一个挑战。
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引用次数: 0
Aptamers as a Potential Therapeutic and Screening Molecule for Oral Cancer. 适配体作为口腔癌潜在的治疗和筛选分子。
IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-10 DOI: 10.2174/0109298673356297241208155602
Thangavel Lakshmipriya, Subash C B Gopinath, Dhamodharan Prabhu, Evan T Salim, Makram A Fakhri
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引用次数: 0
Current Scenario in Associating Clinical COVID-19 Biomarkers for Developing Surveillance Platforms. 关联临床COVID-19生物标志物开发监测平台的现状
IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-09 DOI: 10.2174/0109298673331044241031100627
Thangavel Lakshmipriya, Subash C B Gopinath, Yeng Chen, Sreenivasan Sasidharan, Sreeramanan Subramaniam, Ahmad Anas Nagoor Gunny, Umi Fazara Md Ali, M N Salimi, Makram A Fakhri, Evan T Salim, Theivasanthi Thirugnanasambandan

The novel coronavirus that caused the epidemic and pandemic resulting in the acute respiratory illness known as coronavirus disease 2019 (COVID-19) has plagued the world. This is unlike other coronavirus outbreaks that have occurred in the past, such as Middle East respiratory syndrome (MERS) or severe acute respiratory syndrome (SARS). COVID-19 has spread more quickly and posed special challenges due to the lack of appropriate treatments and vaccines. Real-time polymerase chain reaction (RTPCR) and rapid antibody tests (surveillance tests) are the two most used tests (confirmation tests). However, the latter takes hours to complete, and the former may produce false positives. Scientists have invested significant effort to create a COVID-19 diagnostic system that is both highly sensitive and reasonably priced. Early detection of COVID-19 is a major area of focus for sensing devices based on nanomaterials. This overview enhanced insights into potential coronavirus biomarkers and, compared to earlier studies, introduced new avenues. Further, it covers the development of COVID-19 diagnostic systems from an analytical point of view, including clinical markers and their subsequent applications with biosensors.

导致2019冠状病毒病(COVID-19)急性呼吸道疾病流行和大流行的新型冠状病毒困扰着世界。这与过去发生的其他冠状病毒疫情不同,例如中东呼吸综合征(MERS)或严重急性呼吸综合征(SARS)。由于缺乏适当的治疗和疫苗,COVID-19传播速度更快,带来了特殊挑战。实时聚合酶链反应(RTPCR)和快速抗体检测(监测检测)是最常用的两种检测(确诊检测)。然而,后者需要数小时才能完成,而前者可能会产生误报。科学家们投入了巨大的努力,创造了一种既高度敏感又价格合理的COVID-19诊断系统。早期检测COVID-19是基于纳米材料的传感设备的一个主要关注领域。与早期的研究相比,这一综述增强了对潜在冠状病毒生物标志物的认识,并引入了新的途径。此外,它还从分析的角度介绍了COVID-19诊断系统的开发,包括临床标记物及其随后与生物传感器的应用。
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引用次数: 0
Design, Synthesis, Biological Evaluation and Docking Studies of 2-hydroxy-4-benzyloxy Chalcone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease. 2-羟基-4-苄基查尔酮衍生物治疗阿尔茨海默病多功能药物的设计、合成、生物学评价及对接研究
IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-09 DOI: 10.2174/0109298673328877241113091539
Wei Li, Jing Huang, Zhixin Chen, Dan Zhang, Lin He, Yan Guo, Lei Zhong, Chenwu Yang, Chunyan Yang, Mei Zeng, Jiang Zhu, Zhongcheng Cao

Objectives: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, but no drugs can cure this disease. Chalcones possess good antioxidant activity, anti-neuroinflammatory activity, neuroprotective effects, inhibitory effects on Aβ aggregation, and Aβ disaggregation ability. Therefore, chalcones are ideal lead compounds, and the discovery of novel anti-AD agent-based chalcones is necessary.

Methods: Hydroxy groups and aryl benzyl ether groups were introduced into chalcone scaffolds to obtain a series of 2-hydroxyl-4-benzyloxy chalcone derivatives. These derivatives were further synthesized, biologically evaluated, and docked.

Results: Most target derivatives exhibited good anti-AD activities. In particular, compound 11d had excellent inhibitory effects on self-induced Aβ1-42 aggregation (90.8% inhibition rate at 25 μM) and Cu2+ induced Aβ1-42 aggregation (93.4% inhibition rate at 25 μM). In addition, it also exhibited good Aβ1-42 fibril disaggregation ability (64.7% at 25 μM), significant antioxidative activity (ORAC = 2.03 Trolox equivalent), moderate MAO-B inhibition (IC50 = 4.81 μM), selective metal chelation, appropriate BBB permeation, and dramatic anti-neuroinflammatory ability. In addition, compound 11d relieved AD symptoms and protected hippocampal neurons in vivo.

Conclusion: Compound 11d is a promising multifunctional anti-Aβ agent.

目标:阿尔茨海默病(AD)是最常见的神经退行性疾病,但目前尚无药物能够治愈这种疾病。查耳酮具有良好的抗氧化活性、抗神经炎症活性、神经保护作用、抑制 Aβ 聚集作用和 Aβ 分解能力。方法:在查尔酮支架中引入羟基和芳基苄基醚基,得到一系列 2-羟基-4-苄氧基查尔酮衍生物。对这些衍生物进行了进一步合成、生物学评价和对接:结果:大多数目标衍生物都表现出了良好的抗厌氧菌活性。结果:大多数目标衍生物都表现出了良好的抗逆转录酶活性,尤其是化合物 11d 对自身诱导的 Aβ1-42 聚集(25 μM 时抑制率为 90.8%)和 Cu2+ 诱导的 Aβ1-42 聚集(25 μM 时抑制率为 93.4%)有很好的抑制作用。此外,它还表现出良好的 Aβ1-42 纤维分解能力(25 μM 时为 64.7%)、显著的抗氧化活性(ORAC = 2.03 Trolox 当量)、中等程度的 MAO-B 抑制能力(IC50 = 4.81 μM)、选择性金属螯合能力、适当的 BBB 渗透能力和显著的抗神经炎能力。此外,化合物 11d 还能缓解 AD 症状,保护体内海马神经元:结论:化合物 11d 是一种很有前景的多功能抗 Aβ 剂。
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引用次数: 0
Structural Modifications and Prospects of Histone Deacetylase (HDAC) Inhibitors in Cancer. 组蛋白去乙酰化酶(HDAC)抑制剂在癌症中的结构修饰与展望。
IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-09 DOI: 10.2174/0109298673332285241104091609
Yu Chen, Jiahong Su, Sha Li, Feier Chen, Yan Zhang, Xingyue Wang, Yinping Zhang, Xiang Wang, Zijun Yuan, Siqi Ren, Xinyu He, Yueshui Zhao, Xu Wu, Mingxing Li, Fukuan Du, Shuai Deng, Jing Shen, Zhangang Xiao

Histone deacetylases (HDACs) play a crucial role in the regulation of cancer progression and have emerged as key targets for antitumor therapy. Histone Deacetylase Inhibitors (HDACis) effectively suppress tumor cell proliferation, induce apoptosis, and cause cell cycle arrest, demonstrating broad-spectrum antitumor activity. This article primarily focuses on enhancing the selectivity of HDACis through structural modification using natural compounds. It provides detailed insights into the structure modification of histone deacetylase 8 (HDAC8) and histone deacetylase 10 (HDAC10), as well as dual-- target inhibitors and their pharmacological effects. Furthermore, conventional HDAC inhibitors are susceptible to off-target effects and the development of drug resistance. Our research focuses on augmenting the targeting specificity of HDAC inhibitors through their combination with proteolysis targeting chimera (PROTAC). Lastly, the latest advancements in clinical research on HDAC inhibitors were summarized, revealing that these inhibitors possess limitations in their clinical applications due to intrinsic or acquired resistance. Consequently, this article primarily focuses on summarizing the current status and prospects of structural modifications for HDAC inhibitors, with the aim of inspiring researchers to develop novel HDAC inhibitors exhibiting enhanced activity for improved application in clinical research.

组蛋白去乙酰化酶(hdac)在癌症进展的调控中起着至关重要的作用,并已成为抗肿瘤治疗的关键靶点。组蛋白去乙酰化酶抑制剂(HDACis)能有效抑制肿瘤细胞增殖,诱导细胞凋亡,引起细胞周期阻滞,具有广谱的抗肿瘤活性。本文主要研究利用天然化合物对HDACis进行结构修饰,从而提高其选择性。详细介绍了组蛋白去乙酰化酶8 (HDAC8)和组蛋白去乙酰化酶10 (HDAC10)的结构修饰,以及双靶点抑制剂及其药理作用。此外,传统的HDAC抑制剂易受脱靶效应和耐药性的影响。我们的研究重点是通过与蛋白水解靶向嵌合体(PROTAC)结合来增强HDAC抑制剂的靶向特异性。最后,总结了HDAC抑制剂的最新临床研究进展,揭示了这些抑制剂由于内在或获得性耐药而在临床应用中存在局限性。因此,本文主要综述了HDAC抑制剂结构修饰的现状和前景,旨在启发研究人员开发具有增强活性的新型HDAC抑制剂,以改善其在临床研究中的应用。
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引用次数: 0
FDA Approves Inavolisib Combo for PIK3CA-Mutated, HR+ Breast Cancer. FDA批准Inavolisib组合治疗pik3ca突变的HR+乳腺癌
IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-08 DOI: 10.2174/0109298673365863250101070254
Jinwei Zhang
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引用次数: 0
A Review on Branched-Chain Amino Acid Aminotransferase (BCAT) Inhibitors: Current Status, Challenges and Perspectives. 支链氨基酸转氨酶(BCAT)抑制剂的研究进展:现状、挑战与展望
IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-08 DOI: 10.2174/0109298673320136241024054435
Xiansheng Zhang, Xinyuan Zhu, Yong Li, Yan Li, Wen Luo, Maaz Khan, Jiamin Pan, Hong Pan, Hua Xie, Guilong Zhao

Branched-chain amino acids (BCAAs) are essential amino acids for humans and play an indispensable role in many physiological and pathological processes. Branched-chain amino acid aminotransferase (BCAT) is a key enzyme that catalyzes the metabolism of BCAAs. BCAT is upregulated in many cancers and implicated in the development and progress of some other diseases, such as metabolic and neurological diseases; and therefore, targeting BCAT might be a potential therapeutic approach for these diseases. There are two isoforms of BCAT, i.e., cytoplasmic BCAT1 (or BCATc) and mitochondrial BCAT2 (or BCATm). The discovery of BCAT inhibitors was initiated by Warner-Lambert, a subsidiary of Pfizer, in 2000, followed by many other pharmaceutical companies, such as GlaxoSmithKline (GSK), Ergon, Icagen, Agios, and Bayer. Strategies of high-throughput screening (HTS), DNA-Encoded library technology (ELT), and fragment-based screening (FBS) have been employed for hit identification, followed by structural optimization. Despite low selectivity, both BCAT1 and BCAT2 selective inhibitors were individually developed, each with a few chemical structural classes. The most advanced BCAT1 inhibitor is BAY-069, discovered by Bayer, which has a potent enzymatic inhibitory activity against BCAT1 and a decent in vitro and in vivo pharmacokinetic profile but displayed weaker cellular inhibitory activity and almost no anti-proliferative activity. There are no BCAT inhibitors currently under investigation in clinical trials. Further studies are still needed to discover BCAT inhibitors with a more druggable profile for proof of concept. This review focuses on the latest progress of studies on the understanding of the physiology and pathology of BCAT and the discovery and development of BCAT inhibitors. The structure-activity relationship (SAR) and the druggability, and the challenges of BCAT inhibitors are discussed, with the aim of inspiring the discovery and development of BCAT inhibitors in the future.

支链氨基酸(BCAAs)是人体必需氨基酸,在许多生理和病理过程中起着不可缺少的作用。支链氨基酸转氨酶(BCAT)是催化支链氨基酸代谢的关键酶。BCAT在许多癌症中上调,并与其他一些疾病(如代谢和神经疾病)的发生和进展有关;因此,靶向BCAT可能是治疗这些疾病的潜在方法。BCAT有两种亚型,即细胞质BCAT1(或BCATc)和线粒体BCAT2(或BCATm)。BCAT抑制剂的发现是由辉瑞公司的子公司Warner-Lambert于2000年率先发现的,随后许多其他制药公司,如葛兰素史克(GSK), Ergon, Icagen, Agios和拜耳。采用高通量筛选(HTS)、dna编码文库技术(ELT)和基于片段的筛选(FBS)策略进行命中识别,然后进行结构优化。尽管选择性较低,但BCAT1和BCAT2选择性抑制剂都是单独开发的,每种抑制剂都具有少量的化学结构类。目前最先进的BCAT1抑制剂是拜耳公司发现的BAY-069,它对BCAT1具有较强的酶促抑制活性,体外和体内药代动力学谱也较好,但细胞抑制活性较弱,几乎没有抗增殖活性。目前还没有BCAT抑制剂在临床试验中进行研究。还需要进一步的研究来发现BCAT抑制剂具有更可药物化的特征,以证明其概念。本文就BCAT的生理病理认识和BCAT抑制剂的发现与开发等方面的最新研究进展作一综述。本文对BCAT抑制剂的构效关系、可药物性和面临的挑战进行了讨论,以期对BCAT抑制剂的发现和开发有所启发。
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引用次数: 0
RNA Modification and Digestive Tract Tumors: A Review. RNA修饰与消化道肿瘤研究进展。
IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-08 DOI: 10.2174/0109298673350007241031025153
Yafeng Liu, Shujun Zhang, Kaijie Liu, Xinyu Gu, Xinjun Hu

Gastrointestinal tumors, including colorectal and liver cancer, are among the most prevalent and lethal solid tumors. These malignancies are characterized by worsening prognoses and increasing incidence rates. Traditional therapeutic approaches often prove ineffective. Recent advancements in high-throughput sequencing and sophisticated RNA modification detection technologies have uncovered numerous RNA chemical alterations significantly associated with the pathogenesis of various diseases, notably cancer. These discoveries have opened new avenues for therapeutic intervention. This article delves into epigenetic modifications, with a particular emphasis on RNA alterations such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), 1-methyladenosine (m1A), 7-methylguanosine (m7G), and N4-acetylcysteine (ac4C). It examines the functions and mechanisms of action of regulatory entities known as "Writers," "Readers," and "Erasers" to these modifications. Additionally, it outlines various methodologies for detecting these RNA modifications. Conventional techniques include radioactive isotope incorporation, two-dimensional thin-layer chromatography (2D-TLC), mass spectrometry, and immunological detection methods. Specialized methods such as bisulfite sequencing and reverse transcription stops are also discussed. Furthermore, the article underscores the significance of these modifications in the development, progression, and therapeutic targeting of gastrointestinal tumors, including esophageal, gastric, colorectal, liver, and pancreatic cancers. This exploration provides foundational insights for enhancing diagnostic accuracy, treatment efficacy, and prognostic assessment in gastrointestinal oncology.

胃肠道肿瘤,包括结肠直肠癌和肝癌,是最常见和最致命的实体肿瘤之一。这些恶性肿瘤的特点是预后恶化和发病率增加。传统的治疗方法往往被证明无效。高通量测序和复杂RNA修饰检测技术的最新进展揭示了许多与各种疾病(特别是癌症)发病机制显著相关的RNA化学改变。这些发现为治疗干预开辟了新的途径。本文深入研究了表观遗传修饰,特别强调RNA的改变,如n6 -甲基腺苷(m6A), 5-甲基胞嘧啶(m5C), 1-甲基腺苷(m1A), 7-甲基鸟苷(m7G)和n4 -乙酰半胱氨酸(ac4C)。它检查了被称为“作家”、“读者”和“橡皮擦”的监管实体对这些修改的功能和作用机制。此外,它概述了检测这些RNA修饰的各种方法。传统的技术包括放射性同位素掺入、二维薄层色谱(2D-TLC)、质谱和免疫检测方法。专门的方法,如亚硫酸盐测序和逆转录停止也进行了讨论。此外,本文强调了这些修饰在胃肠道肿瘤(包括食管癌、胃癌、结直肠癌、肝癌和胰腺癌)的发生、进展和治疗靶向中的重要意义。这一探索为提高胃肠道肿瘤的诊断准确性、治疗疗效和预后评估提供了基础见解。
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Current medicinal chemistry
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