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Synthesis, Structural Modification, and Antismall Cell Lung Cancer Activity of 3-Arylisoquinolines with Dual Inhibitory Activity on Topoisomerase I and II 具有拓扑异构酶I和II双重抑制活性的3-芳基异喹啉类化合物的合成、结构修饰及抗小细胞肺癌活性
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-01-22 DOI: 10.1021/acs.jmedchem.4c02689
Xuemei Deng, Yuying Wang, Xiongqi Yang, Quanwei Yu, Ridong Huang, Hai Chen, Weimin Li, Yang He
To overcome the compensatory effect between Topo I and II, one of the reasons accounting for the resistance of SCLC patients, we are pioneering the use of 3-arylisoquinolines to develop dual inhibitors of Topo I/II for the management of SCLC. A total of 46 new compounds were synthesized. Compounds 3g (IC50 = 1.30 μM for NCI-H446 cells and 1.42 μM for NCI-H1048 cells) and 3x (IC50 = 1.32 μM for NCI-H446 cells and 2.45 μM for NCI-H1048 cells) were selected for detailed pharmacological investigation, due to their outstanding cytotoxicity and dual Topo I and II inhibitory activity. 3g and 3x effectively prevent SCLC cell proliferation, invasion, and migration in vitro, byinducing mitochondrial apoptosis and inhibiting the PI3K/Akt/mTOR pathway. Their in vivo tumor inhibition rate is comparable to etoposide with lower toxicity. These results indicated their potential therapeutic values as dual Topo I and II inhibitors for treating SCLC.
为了克服Topo I和II之间的代偿作用,这是SCLC患者耐药的原因之一,我们正在率先使用3-芳基异喹啉类药物开发Topo I/II的双重抑制剂来治疗SCLC。共合成了46个新化合物。选择化合物3g (NCI-H446细胞IC50 = 1.30 μM, NCI-H1048细胞IC50 = 1.42 μM)和3x (NCI-H446细胞IC50 = 1.32 μM, NCI-H1048细胞IC50 = 2.45 μM)进行详细的药理研究,因为它们具有出色的细胞毒性和双Topo I和II抑制活性。3g和3x通过诱导线粒体凋亡和抑制PI3K/Akt/mTOR通路,有效地阻止SCLC细胞的体外增殖、侵袭和迁移。其体内肿瘤抑制率与依托泊苷相当,毒性更低。这些结果表明它们作为双Topo I和II抑制剂治疗SCLC的潜在治疗价值。
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引用次数: 0
Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve 第二代pik5体内化学探针的研制
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-01-22 DOI: 10.1021/acs.jmedchem.4c02531
Sophia M. Min, Frances M. Bashore, Jeffery L. Smith, Tammy M. Havener, Stefanie Howell, Haoxi Li, Rafael M. Couñago, Konstantin I. Popov, Alison D. Axtman
We optimized our highly potent and cell-active chemical probe for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), SGC-PIKFYVE-1, resulting in compounds with improved potency and demonstrated in vivo stability. Use of an in-cell, kinome-wide selectivity panel allowed for confirmation of excellent in-cell selectivity of our lead compound, 40, and another promising analogue, 46. Evaluation of the pharmacokinetic (PK) profiles of these two compounds revealed that both are well tolerated systemically and orally bioavailable. Coupled with its subnanomolar cellular potency and impressive selectivity in cells, the long half-life of 40 makes it an ideal candidate for the evaluation of the consequences of PIKfyve inhibition in vivo. PIKfyve inhibition has been investigated clinically for indications including rheumatoid arthritis, Crohn’s disease, COVID-19, and ALS using a single compound (apilimod), supporting the development of orthogonal PIKfyve inhibitors with in vivo stability.
我们优化了高效、细胞活性的磷脂酰肌醇-3-磷酸5激酶(PIKfyve)化学探针SGC-PIKFYVE-1,得到的化合物具有更高的效价和体内稳定性。使用细胞内kinomin -wide选择性面板可以确认我们的先导化合物40和另一种有前途的类似物46具有出色的细胞内选择性。对这两种化合物的药代动力学(PK)谱的评估显示,它们都具有良好的全身耐受性和口服生物利用度。再加上其在细胞中的亚纳摩尔细胞效力和令人印象深刻的选择性,40年的长半衰期使其成为评估体内抑制PIKfyve后果的理想候选者。PIKfyve已在临床研究中用于类风湿性关节炎、克罗恩病、COVID-19和ALS等适应症,使用单一化合物(apilimod),支持开发具有体内稳定性的正交PIKfyve抑制剂。
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引用次数: 0
Effects of Heparan Sulfate Trisaccharide Containing Oleanolic Acid in Attenuating Hyperphosphorylated Tau-Induced Cell Dysfunction Associated with Alzheimer’s Disease 含齐墩果酸硫酸肝素三糖在减轻与阿尔茨海默病相关的过度磷酸化tau诱导的细胞功能障碍中的作用
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-01-22 DOI: 10.1021/acs.jmedchem.4c02563
Sanyong Zhu, Zhenfeng Song, April Sweet Tapayan, Kartikey Singh, Kuang-Wei Wang, Hsiao-Tien Chien Hagar, Jicheng Zhang, Hyunbae Kim, Patty Thepsuwan, Min-Hao Kuo, Kezhong Zhang, Hien M. Nguyen
Alzheimer’s disease (AD) is the most common form of dementia, marked by progressive brain degeneration and cognitive decline. A major pathological feature of AD is the accumulation of hyperphosphorylated tau (p-tau) in the form of neurofibrillary tangles (NFTs), which leads to neuronal death and neurodegeneration. P-tau also induces endoplasmic reticulum (ER) stress and activates the unfolded protein response, causing inflammation and apoptosis. Additionally, p-tau spreads in the brain through interactions with heparan sulfate (HS) proteoglycans, promoting aggregation and internalization. Targeting the tau–HS interaction offers a potential therapeutic strategy for AD. We present a novel HS mimetic with a lipophilic oleanolic acid linker and a sulfated trisaccharide, which shows strong cytoprotective effects against p-tau. Moreover, this compound alleviates p-tau-induced ER stress and inflammation. Molecular docking studies indicate that the conjugation of oleanolic acid enhances binding between the ligand and tau protofilament cores, facilitating protective interactions. These findings provide a foundation for the development of novel HS mimetics, enabling further investigation of tau-HS interactions in AD and other tauopathies.
阿尔茨海默病(AD)是最常见的痴呆症,其特征是大脑进行性变性和认知能力下降。AD的一个主要病理特征是过度磷酸化的tau (p-tau)以神经原纤维缠结(nft)的形式积累,导致神经元死亡和神经变性。P-tau也诱导内质网应激并激活未折叠蛋白反应,引起炎症和细胞凋亡。此外,p-tau通过与硫酸肝素(HS)蛋白聚糖的相互作用在大脑中扩散,促进聚集和内化。靶向tau-HS相互作用为AD提供了一种潜在的治疗策略。我们提出了一种新的HS模拟物,它具有亲脂齐墩果酸连接体和硫酸三糖,对p-tau具有很强的细胞保护作用。此外,该化合物还能减轻p-tau诱导的内质网应激和炎症。分子对接研究表明齐墩果酸的偶联增强了配体与tau原丝核之间的结合,促进了保护性相互作用。这些发现为开发新的HS模拟物提供了基础,使进一步研究AD和其他tau-HS相互作用成为可能。
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引用次数: 0
Correction to “Development of BromoTag: A “Bump-and-Hole”–PROTAC System To Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins” 更正“BromoTag的开发:一种“Bump-and-Hole”-PROTAC系统,可诱导标记靶蛋白的有效、快速和选择性降解”
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-01-22 DOI: 10.1021/acs.jmedchem.5c00108
Adam G. Bond, Conner Craigon, Kwok-Ho Chan, Andrea Testa, Athanasios Karapetsas, Rotimi Fasimoye, Thomas Macartney, J. Julian Blow, Dario R. Alessi, Alessio Ciulli
It has come to our attention that two of the Western blot panels in Figure 5, namely, the “Brd4 short” lanes for ET-OMZ1 (<b>23</b>) and ET-OARV-771 (<b>25</b>) were the same. This arose as a result of an honest mistake when choosing panels used from the corresponding uncropped blots. This is clear from the relevant Supplemental Figure (Figure S7, page 16 in the Supporting Information), which shows all the full-length uncropped blots that were used to prepare the final Figure 5. The figure has been corrected and shows the correct panel corresponding to “Brd4 short” for ET-OMZ1 (<b>23</b>). The panel corresponding to “Brd4 short” for compound ET-OARV-771 (<b>25</b>) was correct and thus did not require changes. Having recognized this issue, we decided to go over ALL the material again and found a few other minor issues. We discovered that the “Brd4 short” panel for ME-OARV-771 (<b>24</b>) was also incorrectly chosen from the corresponding uncropped blot (see the same relevant Supplemental Figure S7, on page 16 in the Supporting Information). This has now been corrected. We have also found that the “tubulin” panels for ET-MZ1 (<b>19</b>), ME-ARV-771 (<b>20</b>) and ET-ARV-771 (<b>21</b>) were incorrectly cropped to show 8 lanes instead of the 7 in question, keeping an additional irrelevant lane on the far right of the panels. We have now recropped these panels to remove this lane. Figure 5 with the corrected panels is shown above. The data analysis and conclusions are not affected by these mistakes. Page 15496 (middle of right column). The identity of the template backbone of the BromoTag vector donor was incorrectly quoted as “pcDNA5”. The correct vector is “pMK-RQ” as follows. HEK293 cells were transfected using a Fugene HD transfection reagent (Madison, Wisconsin, United States) or lipofectamine 2000 (Madison, Wisconsin, United States) simultaneously with three custom vectors including a px335 vector (Addgene) containing a U6-snRNA and Cas9D10A expression cassette, a pBABED vector (MRC PPU, Dundee University) harboring another U6-sgRNA and puromycin expression cassette, and finally a pMK-RQ vector containing an eGFP-P2A-BromoTag-Brd2 donor knock-in sequence. Page 15498 (bottom of left column). The size of the tissue culture plate used was incorrectly quoted as “100 cm”. The correct size is “10 cm” as follows. CRISPR-modified BromoTag-Brd2 HEK293 cells (5 × 10<sup>6</sup>) were seeded on a 10 cm plate 24 h before treatment. We have revised the Supporting Information to add text to clarify the number of biological replicates (<i>n</i>) that were performed for each experiment. We have now also realized that the “Brd4 antibody” panel for PROTAC AGB1 (<b>46</b>) at the top right of Supplementary Figure 9 on page 24 in the Supporting Information (and the corresponding tubulin loading control) was from a different biological replicate of the same experiment than the one chosen in the corresponding main text figure (Figure 6, on page 15489). This has no
我们注意到图5中的两个Western blot图,即ET-OMZ1(23)和ET-OARV-771(25)的“Brd4短”通道是相同的。这是由于在从相应的未裁剪的斑点中选择面板时犯了一个诚实的错误。从相关的补充图(图S7,第16页的支持信息)中可以清楚地看出这一点,该图显示了用于准备最终图5的所有全长未裁剪的印迹。图中已更正,为ET-OMZ1(23)“Brd4 short”对应的正确面板。化合物ET-OARV-771(25)对应的“Brd4 short”面板是正确的,因此不需要更改。认识到这个问题后,我们决定再次检查所有材料,并发现了其他一些小问题。我们发现ME-OARV-771(24)的“Brd4 short”面板也被错误地从相应的未裁剪的印迹中选择(参见支持信息第16页相同的相关补充图S7)。现在这个问题已经得到了纠正。我们还发现,ET-MZ1 (19), ME-ARV-771(20)和ET-ARV-771(21)的“微管蛋白”面板被错误地切割为显示8个车道而不是7个车道,在面板的最右侧保留了一个额外的无关车道。我们现在已经将这些面板拆下,以移除这条车道。图5与更正面板如上所示。这些错误不影响数据分析和结论。第15496页(右栏中间)。BromoTag载体供体的模板主干的身份被错误地引用为“pcDNA5”。正确的矢量是“pMK-RQ”,如下所示。用Fugene HD转染试剂(Madison, Wisconsin,美国)或lipofectamine 2000 (Madison, Wisconsin,美国)同时转染HEK293细胞,同时转染三种定制载体,包括含有U6-snRNA和Cas9D10A表达盒的px335载体(Addgene),含有另一个U6-sgRNA和purromycin表达盒的pBABED载体(MRC PPU, Dundee University),最后是含有eGFP-P2A-BromoTag-Brd2供体敲入序列的pMK-RQ载体。第15498页(左栏底部)。使用的组织培养板的大小被错误地引用为“100cm”。正确的尺寸如下“10cm”处理前24 h,将crispr修饰的BromoTag-Brd2 HEK293细胞(5 × 106)接种于10 cm板上。我们已经修改了支持信息,以增加文本来澄清每个实验进行的生物重复数量(n)。我们现在也意识到,支持信息第24页补充图9右上方的PROTAC AGB1(46)的“Brd4抗体”面板(以及相应的微管蛋白加载控制)来自同一实验的不同生物重复,而不是相应的主要文本图(图6,第15489页)中选择的生物重复。这已在支持信息中更正。我们还检测到在第27页的辅助信息中,补充图15中的“cis-MZ1”和“MZ1(1)”标签不小心被调换了。这已在支持信息中更正。支持信息可在https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c00108免费获取。BromoTag degron组分的DNA序列分析结PCR;杂合子BromoTag-Brd2 Hek293细胞株中eGFP-P2A-BromoTag全长的基因分型PROTACs 18-25对Brd4长、短、Brd3、Brd2和Brd4BD2 L387A的蛋白降解谱;Brd4BD2 L387A和Brd2的AGB1(46)、AGB2(47)和AGB3(48)蛋白降解谱;原始的未裁剪的Western blot图像;化合物46 ~ 48和52的HPLC-HRMS痕量分析化合物46-48和52的核磁共振光谱(PDF)更正“BromoTag的开发:一个“凹凸孔”- protac系统诱导有效,快速和选择性降解标记目标蛋白”2视图0共享0下载大多数电子支持信息文件可在没有订阅ACS网络版的情况下使用。这些文件可以通过文章下载用于研究用途(如果相关文章有公共使用许可链接,该许可可以允许其他用途)。如有其他用途,可通过RightsLink权限系统http://pubs.acs.org/page/copyright/permissions.html向ACS申请。这篇文章尚未被其他出版物引用。
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引用次数: 0
Design, Synthesis, and SAR of Covalent KIT and PDGFRA Inhibitors─Exploring Their Potential in Targeting GIST 共价KIT和PDGFRA抑制剂的设计、合成和SAR──探索其靶向GIST的潜力
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-01-22 DOI: 10.1021/acs.jmedchem.4c02472
Tom Schulz, Rajesh Gontla, Alina Teuber, Maria Beerbaum, Benjamin S. Fletcher, Thomas Mühlenberg, Helena Kaitsiotou, Julia Hardick, Kirujan Jeyakumar, Marina Keul, Matthias P. Müller, Sonja Sievers, Sebastian Bauer, Daniel Rauh
Gastrointestinal stromal tumors (GIST), driven by KIT and PDGFRA mutations, are the most common mesenchymal tumors of the gastrointestinal tract. Although tyrosine kinase inhibitors (TKIs) have advanced treatment, resistance mutations and off-target toxicity limit their efficacy. This study develops covalent TKIs targeting drug-resistant GIST through structure-based design, synthesis, and biological evaluation. SAR studies provided key insights into mutant KIT and PDGFRA interactions, and the first crystal structure of PDGFRA bound to a covalent inhibitor is reported. These findings highlight the promise of covalent inhibitors for overcoming resistance and advancing safer, more effective therapies for advanced GIST.
胃肠道间质瘤(GIST)是由KIT和PDGFRA突变驱动的最常见的胃肠道间质肿瘤。虽然酪氨酸激酶抑制剂(TKIs)有先进的治疗方法,但耐药突变和脱靶毒性限制了它们的疗效。本研究通过基于结构的设计、合成和生物学评价,开发了靶向耐药GIST的共价TKIs。SAR研究提供了突变体KIT和PDGFRA相互作用的关键见解,并报道了PDGFRA与共价抑制剂结合的第一个晶体结构。这些发现突出了共价抑制剂在克服耐药性和推进更安全、更有效的晚期GIST治疗方面的前景。
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引用次数: 0
Macrocyclization as a Strategy for Kinetic Solubility Improvement: A Comparative Analysis of Matched Molecular Pairs 大环化作为一种改善动力学溶解度的策略:匹配分子对的比较分析
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-01-22 DOI: 10.1021/acs.jmedchem.4c01822
Carlo Walz, Moritz Spiske, Magnus Walter, Benjamin-Luca Keller, Mario Mezler, Carolin Hoft, Frauke Pohlki, Stella Vukelić, Felix Hausch
In recent years, rationally designed macrocycles have emerged as promising therapeutic modalities for challenging drug targets. Macrocycles can improve affinity, selectivity, and pharmacokinetic (PK) parameters, possibly via providing semirigid, preorganized scaffolds. Nevertheless, how macrocyclization affects PK-relevant properties is still poorly understood. To address this question, we systematically generated and compared 15 matched molecular pairs of macrocycles and structurally similar linear analogs. We found that macrocyclization substantially improves kinetic solubility while not impairing the other measured parameters. We hypothesize that this could arise from “chameleonicity,” which was previously reported for large, natural-product-derived macrocycles. Our results show that the improvement of kinetic solubility is an underappreciated aspect of macrocycles that may facilitate formulation strategies compared to linear analogs to improve bioavailability.
近年来,合理设计的大周期已成为具有挑战性的药物靶点的有希望的治疗方式。大环可以提高亲和力、选择性和药代动力学(PK)参数,可能是通过提供半刚性、预组织的支架。然而,大环化如何影响pk相关性质仍然知之甚少。为了解决这个问题,我们系统地生成并比较了15对匹配的分子对和结构相似的线性类似物。我们发现,大环化大大提高了动力学溶解度,而不损害其他测量参数。我们假设这可能是由“变色性”引起的,这是之前报道的大型天然产物衍生的大周期。我们的研究结果表明,与线性类似物相比,大环的动力学溶解度的改善是一个被低估的方面,这可能有助于制定策略,以提高生物利用度。
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引用次数: 0
Evaluation of Anticancer Activity of Novel and Tumor-Targeted Glutamine-Conjugated Organotin(IV) Compounds in Colorectal Cancer─An In Vitro and In Vivo Study 新型肿瘤靶向谷氨酰胺偶联有机锡(IV)化合物在结直肠癌中的抗癌活性评价──体外和体内研究
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-01-21 DOI: 10.1021/acs.jmedchem.4c01728
Shagun Sharma, Varinder Kaur, Pratibha Duhan, Raghubir Singh, Navneet Agnihotri
Over the years, numerous ligand-based organotin(IV) Schiff base compounds have shown remarkable cytotoxicity and anticancer activities, but their clinical use is restricted by systemic toxicity, prompting the search for targeted therapies. Targeted delivery can be enhanced by exploiting the inherent characteristics of cancer cells such as glutamine addiction, which is essential to support cellular biosynthesis and cell growth to sustain aberrant proliferation. Our previous study revealed glutamine-conjugated organotin(IV) compounds have strong DNA/protein affinities, favorable in silico ADME profiles, and significant antiproliferative activity. In this study, these compounds demonstrated significant cytotoxicity against human colon carcinoma and adenocarcinoma cell lines via the induction of cell cycle arrest and apoptosis. In DMH/DSS-induced experimental colon carcinogenesis, these compounds reduced tumor burden and volume and inhibited cell proliferation and induced apoptosis, with minimal toxicity. Tissue distribution studies revealed selective accumulation in the colon. These findings support their potential as chemotherapeutic candidates for colon cancer.
多年来,许多基于配体的有机锡(IV)希夫碱化合物显示出显著的细胞毒性和抗癌活性,但它们的临床应用受到全身毒性的限制,促使人们寻找靶向治疗方法。靶向递送可以通过利用癌细胞的固有特征(如谷氨酰胺成瘾)来增强,这是支持细胞生物合成和细胞生长以维持异常增殖所必需的。我们之前的研究表明,谷氨酰胺偶联的有机锡(IV)化合物具有很强的DNA/蛋白质亲和力,有利的硅ADME谱,以及显著的抗增殖活性。在本研究中,这些化合物通过诱导细胞周期阻滞和细胞凋亡,对人结肠癌和腺癌细胞系显示出显著的细胞毒性。在DMH/ dss诱导的实验性结肠癌中,这些化合物减少肿瘤负荷和体积,抑制细胞增殖和诱导细胞凋亡,毒性很小。组织分布研究显示在结肠中选择性积累。这些发现支持了它们作为结肠癌化疗候选药物的潜力。
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引用次数: 0
Discovery of Novel Spirocyclic MAT2A Inhibitors Demonstrating High In Vivo Efficacy in MTAP-Null Xenograft Models 新型螺旋环MAT2A抑制剂的发现在mtap无效的异种移植模型中显示出高体内疗效
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-01-21 DOI: 10.1021/acs.jmedchem.4c02634
Sai Yang, Xiaowen Gu, Lei Chen, Weixing Zhu
Synthetic lethality offers a robust strategy for discovering the next generation of precision medicine therapies tailored for molecularly defined patient populations. MAT2A inhibition is synthetically lethal in several cancers that exhibit a homozygous deletion of S-methyl-5′-thioadenosine phosphorylase (MTAP). Herein, we report the identification of novel MAT2A inhibitors featuring a spiral ring to circumvent the C–N atropisomeric chirality utilizing structure-based drug design. The Hit compound 9 exhibited high potency in enzymatic activity (IC50 = 7 nM) and in HCT-116 MTAP(−/−) cell potency (IC50 = 17 nM). Further optimization has led to the identification of two new lead compounds: a brain-penetrant compound, 29–1, and a potent but limited brain-penetrant compound, 39. Both of these lead compounds demonstrate increased plasma drug exposure and exhibit significant efficacy in xenograft models that are depleted of MTAP. We hope that identifying a brain-penetrant MAT2A inhibitor will create new opportunities to explore the potential therapeutic effects of S-adenosylmethionine modulation in the central nervous system.
合成致死性为发现针对分子界定的患者群体的下一代精准医学疗法提供了一种强有力的策略。MAT2A抑制剂对S-甲基-5′-硫代腺苷磷酸酶(MTAP)同基因缺失的几种癌症具有合成致死性。在此,我们报告了利用基于结构的药物设计鉴定出的新型 MAT2A 抑制剂,其特点是利用螺旋环来规避 C-N 异构手性。命中化合物 9 在酶活性(IC50 = 7 nM)和 HCT-116 MTAP(-/-)细胞效力(IC50 = 17 nM)方面表现出很高的效力。通过进一步优化,我们发现了两个新的先导化合物:一个是脑穿刺化合物 29-1,另一个是强效但有限的脑穿刺化合物 39。这两种先导化合物都增加了血浆中的药物暴露量,并在去除了 MTAP 的异种移植模型中表现出显著疗效。我们希望找到一种脑渗透剂 MAT2A 抑制剂,为探索 S-腺苷蛋氨酸调节在中枢神经系统中的潜在治疗效果创造新的机会。
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引用次数: 0
Repurposing Linezolid in Conjunction with Histone Deacetylase Inhibitor Access in the Realm of Glioblastoma Therapies 利奈唑胺联合组蛋白去乙酰化酶抑制剂在胶质母细胞瘤治疗领域的应用
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-01-21 DOI: 10.1021/acs.jmedchem.4c02086
I-Chung Chen, Hong-Yi Lin, Zheng-Yang Liu, Wei-Jie Cheng, Tzu-Yi Yeh, Wen-Bin Yang, Hoang Yen Tran, Mei-Jung Lai, Chung-Han Wang, Tzu-Yuan Kao, Chia-Yang Hung, Ya-Lin Huang, Ke-Chi Liou, Chien-Ming Hsieh, Tsung-I Hsu, Jing-Ping Liou
Since decades after temozolomide was approved, no effective drugs have been developed. Undoubtedly, blood–brain barrier (BBB) penetration is a severe issue that should be overcome in glioblastoma multiforme (GBM) drug development. In this research, we were inspired by linezolid through structural modification with several bioactive moieties to achieve the desired brain delivery. The results indicated that the histone deacetylase modification, referred to as compound 1, demonstrated promising cytotoxic effects in various brain tumor cell lines. Further comprehensive mechanism studies indicated that compound 1 induced acetylation, leading to DNA double-strand breaks, and induced the ubiquitination of RAD51, disrupting the DNA repair process. Furthermore, compound 1 also exhibited dramatic improvement in the orthotopic GBM mouse model, demonstrating its efficacy and satisfying BBB penetration. Therefore, the reported compound 1, provided with an independent therapeutic pathway, satisfying elongation in survival and tumor size reduction, and the ability to penetrate the BBB, was potent to achieve further development.
在替莫唑胺被批准几十年后,还没有开发出有效的药物。毫无疑问,血脑屏障(BBB)渗透是多形性胶质母细胞瘤(GBM)药物开发中需要克服的一个严重问题。在这项研究中,我们受到利奈唑胺的启发,通过几种生物活性成分的结构修饰来实现所需的脑递送。结果表明,组蛋白去乙酰化酶修饰,简称化合物1,在各种脑肿瘤细胞系中显示出有希望的细胞毒作用。进一步的综合机制研究表明,化合物1诱导乙酰化,导致DNA双链断裂,并诱导RAD51泛素化,破坏DNA修复过程。此外,化合物1在原位GBM小鼠模型中也表现出显著的改善作用,表明其有效性并满足血脑屏障渗透。因此,所报道的化合物1具有独立的治疗途径,满足延长生存期和缩小肿瘤大小的要求,并且具有穿透血脑屏障的能力,因此具有进一步发展的潜力。
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引用次数: 0
Strategic Inhibition of CHRM Autoantibodies: Molecular Insights and Therapeutic Potentials in Long COVID CHRM自身抗体的策略抑制:长冠状病毒的分子观察和治疗潜力
IF 7.3 1区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2025-01-21 DOI: 10.1021/acs.jmedchem.4c00691
Abdul Mannan Baig, Sandy Rosko, Beate Jaeger, Joachim Gerlach
In addition to the conventional symptoms reported for COVID-19, it is becoming increasingly clear that patients with long COVID are exhibiting new symptoms due to the emergence of autoantibodies against G-protein-coupled receptors, among which human muscarinic cholinergic receptors (CHRMs) have been prominently reported. With a chronic condition such as long COVID, additional symptoms caused by anti-CHRM autoantibodies (AAbs) have proven to be an added burden on these patients. The origins of these AAbs, their interactions with, and effects on the function of neural and non-neural cells within the nervous system have remained unknown. Furthermore, the specific symptom complex to which they contribute has not been clearly understood. In this context, we address these issues here and suggest methods to combat the autoantibodies that contribute to neurological symptoms in long COVID.
除了COVID-19报告的常规症状外,越来越清楚的是,长COVID患者由于出现针对g蛋白偶联受体的自身抗体而表现出新的症状,其中人类毒蕈碱胆碱能受体(CHRMs)已被突出报道。对于长期COVID等慢性疾病,抗chrm自身抗体(AAbs)引起的额外症状已被证明是这些患者的额外负担。这些抗体的起源、它们与神经系统内神经细胞和非神经细胞的相互作用以及对神经细胞功能的影响仍然未知。此外,它们所导致的具体症状还没有被清楚地理解。在这种情况下,我们在这里解决这些问题,并提出对抗自身抗体的方法,这些抗体会导致长期COVID的神经系统症状。
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引用次数: 0
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