RSC medicinal chemistry最新文献_第2页

The pan-cancer analysis of LRG1 and its potential role in kidney renal clear cell carcinoma.

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-02-11 DOI: 10.1039/d4md00940a

Ziwen Lei, Shiyu Song, Yizhuo Geng, Bian Liu, Yongzheng Li, Huan Min, Saiyang Zhang, Yingqiu Qi

{"title":"The pan-cancer analysis of LRG1 and its potential role in kidney renal clear cell carcinoma.","authors":"Ziwen Lei, Shiyu Song, Yizhuo Geng, Bian Liu, Yongzheng Li, Huan Min, Saiyang Zhang, Yingqiu Qi","doi":"10.1039/d4md00940a","DOIUrl":"10.1039/d4md00940a","url":null,"abstract":"Leucine-rich α-2 glycoprotein 1 (LRG1) is a secreted glycoprotein implicated in various diseases, yet its role across multiple cancers remains insufficiently explored. Consequently, we conducted a comprehensive bioinformatics analysis, exploring LRG1 expression patterns, prognostic implications, and potential therapeutic associations in a pan-cancer context. Additionally, we collected gene expression and clinical data from patients with kidney renal clear cell carcinoma (KIRC) from TCGA, conducting gene set enrichment analysis (GSEA) and Cox proportional hazards regression analysis to explore the potential regulatory role of LRG1 in KIRC. Our study revealed that LRG1 expression is upregulated in 18 cancer types, with elevated levels correlating with poor prognostic outcomes in several cancers, notably KIRC. Epigenetic analysis showed hypomethylation in the LRG1 promoter region, potentially contributing to the overexpression of LRG1. Moreover, LRG1 expression was linked to immunotherapeutic responses and altered drug sensitivities, particularly influencing the efficacy of tyrosine kinase inhibitors. In KIRC, high LRG1 expression was associated with the activation of key pathways, including angiogenesis, epithelial-mesenchymal transition (EMT), and hypoxia signalling. We identified key gene pairs interacting with LRG1 in KIRC, including CARD14 and CYP8B1, with CARD14 overexpression correlating with poorer clinical outcomes and CYP8B1 indicating a favourable prognosis. In conclusion, LRG1 emerges as a potential biomarker for prognosis and immunotherapy responsiveness in both pan-cancer and KIRC contexts. This study provides a theoretical foundation for further research on the therapeutic potential of target regulating LRG1 in cancer treatment.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11848403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AlbiCDN: albumin-binding amphiphilic STING agonists augment the immune activity for cancer immunotherapy.

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-02-11 DOI: 10.1039/d4md00475b

Shao-Hua Zhuo, Xi Chen, Lang Zhao, Tian-Yang Wang, Jing-Yun Su, Tao Yang, Lijun Yang, Fei Dong, Yu-Fen Zhao, Yan-Mei Li

{"title":"AlbiCDN: albumin-binding amphiphilic STING agonists augment the immune activity for cancer immunotherapy.","authors":"Shao-Hua Zhuo, Xi Chen, Lang Zhao, Tian-Yang Wang, Jing-Yun Su, Tao Yang, Lijun Yang, Fei Dong, Yu-Fen Zhao, Yan-Mei Li","doi":"10.1039/d4md00475b","DOIUrl":"10.1039/d4md00475b","url":null,"abstract":"The stimulator of interferon genes (STING) has been an attractive target in cancer immunotherapy. However, natural ligand cyclic dinucleotides (CDNs) and CDN derivatives have demonstrated limited efficacy in clinical trials. This limitation stems from the inherent structure of CDNs, which leads to enzymatic degradation, poor cell internalisation, rapid clearance from the tumour microenvironment, and dose-limiting toxicity. In this study, we developed an amphipathic STING agonist, termed albumin-binding CDNs (AlbiCDNs), to enhance the efficacy of c-di-GMP (CDG) via a lipid-conjugated strategy. The lipid provided a platform for albumin hitchhiking, which facilitated the cytoplasmic delivery of CDG without the use of any exogenous components. In addition, incorporating a stimuli-responsive lipid motif further enhanced the cellular release of CDG. Our results indicated that CDG-1C14, an AlbiCDN, efficiently stimulated the maturation and activation of antigen-presenting cells through STING activation. Furthermore, CDG-1C14 exhibited a significant inhibitory effect on the tumour therapeutic model. Therefore, AlbiCDN is a potent platform for cancer immunotherapy that can expedite clinical translation.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11848399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Insights from protein frustration analysis of BRD4-cereblon degrader ternary complexes show separation of strong from weak degraders.

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-02-10 DOI: 10.1039/d4md00962b

Tianyi Yang, Elizaveta Mukhaleva, Wenyuan Wei, Dahlia Weiss, Ning Ma, Veerabahu Shanmugasundaram, Nagarajan Vaidehi

{"title":"Insights from protein frustration analysis of BRD4-cereblon degrader ternary complexes show separation of strong from weak degraders.","authors":"Tianyi Yang, Elizaveta Mukhaleva, Wenyuan Wei, Dahlia Weiss, Ning Ma, Veerabahu Shanmugasundaram, Nagarajan Vaidehi","doi":"10.1039/d4md00962b","DOIUrl":"10.1039/d4md00962b","url":null,"abstract":"PROteolysis TArgeting Chimeras (PROTACs), also known as ligand-directed degraders (LDDs), are an innovative class of small molecules that leverage the ubiquitin-proteasome system to induce the degradation of target proteins. Structure based design methods are not readily applicable for designing LDDs due to the dynamic nature of the ternary complexes. This study investigates the dynamic properties of five LDD-mediated BRD4-cereblon complexes, focusing on the challenges of evaluating linker efficiency due to the difficulty in identifying suitable computational metrics that correlate well with the cooperativity or degradation propensity of LDDs. We uncovered that protein frustration, a concept originally developed to understand protein folding, calculated for the residues in the protein-protein interface of the LDD-mediated ternary complexes recapitulate the strength of degradation of the LDDs. Our findings indicated that hydrophobic residues in the interface are among the highly frustrated residues pairs, and they are crucial in distinguishing strong degraders from weak ones. By analyzing frustration patterns, we identified key residues and interactions critical to the effectiveness of the ternary complex. These insights provide practical guidelines for designing and prioritizing more efficient degraders, paving the way for the development of next-generation LDDs with improved therapeutic potential.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11851170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of a novel allosteric binding site on the catalytic domain of NF-κB inducing kinase (NIK). 鉴定 NF-κB 诱导激酶（NIK）催化结构域上的新型异构结合位点。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-02-07 DOI: 10.1039/d4md00963k

Jared J Anderson, Daniel A Harki

引用次数: 0

Synthesis of fluorinated tubastatin A derivatives with bi-, tri-, and tetracyclic cap groups: molecular docking with HDAC6 and evaluation of in vitro antitumor activity.

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-02-06 DOI: 10.1039/d4md00898g

Huaxin Luo, Zheng Huang, Xiangdong Mo, Chunmei Long, Kaiyuan Wang, Rong Deng, Xiaofeng Zhu, Zhuo Zeng

{"title":"Synthesis of fluorinated tubastatin A derivatives with bi-, tri-, and tetracyclic cap groups: molecular docking with HDAC6 and evaluation of in vitro antitumor activity.","authors":"Huaxin Luo, Zheng Huang, Xiangdong Mo, Chunmei Long, Kaiyuan Wang, Rong Deng, Xiaofeng Zhu, Zhuo Zeng","doi":"10.1039/d4md00898g","DOIUrl":"https://doi.org/10.1039/d4md00898g","url":null,"abstract":"Herein, we report the synthesis of 16 tubastatin A derivatives with fluorinated bi-, tri-, and tetracyclic cap groups. Most derivatives show strong in vitro antitumor activity, achieving micromolar or sub-micromolar efficacy. The most promising compound, 4-(6-bromo-3,3-difluoro-1,2,3,4-tetrahydro-9H-carbozol-9-yl)methyl)-N-hydroxybenzamide (14f), demonstrated potent anti-proliferative effects against human nasopharyngeal carcinoma cells (SUNE1) and human breast cancer cells (MDA-MB-231), with IC50 values of 0.51 μM and 0.52 μM, respectively. Notably, compound 4-((8-fluoroindeno[2,1-b]indol-5(6H)-yl)-N-hydroxybenzamide (13c) exhibited significant anti-proliferative activity against pancreatic cancer cells (SW1990), with an IC50 of 2.06 μM and low cytotoxicity to normal cells. Overall, variations in the cap group from bi- to tri-, then to tetracyclic, and the introduction of fluorinated groups enhance the antitumor activity of these derivatives. Among them, difluoromethyl-modified tricyclic derivatives show a broad spectrum in vitro antitumor effect. Molecular docking studies indicate that these derivatives bind to Histone Deacetylase 6 (HDAC6) at low binding energies, ranging from -6.54 to -9.84 kcal mol-1, through metal complexation, hydrogen bonding, π-π stacking, and π-cation interactions, which correlates with their good antitumor activity. Compound 4-((2-fluoro-5,6-dihydro-7H-benzo[c]carbazol-7-yl)methyl)-N-hydroxybenzamide (13a) with the lowest binding energy of -9.84 kcal mol-1 exhibited the best in vitro antitumor activity against MCF-7, with IC50 of 1.98 μM.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Feasibility of F-18 radiolabeled brain-penetrable bi-specific antibody radioligands for in vivo PET imaging of tauopathy. F-18放射性标记脑穿透性双特异性抗体放射性配体用于锥体病体内正电子发射计算机断层成像的可行性。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-02-06 DOI: 10.1039/d4md00866a

Andrew C Kelleher, Brandon Richardson, Vinay Kumar Banka, Alex Kazior, Cathy Tan, Sabrina Chan, Rumaish Khastgir, Hao Hu, Zakia Youss, Orin Mishkit, Yu-Shin Ding

{"title":"Feasibility of F-18 radiolabeled brain-penetrable bi-specific antibody radioligands for in vivo PET imaging of tauopathy.","authors":"Andrew C Kelleher, Brandon Richardson, Vinay Kumar Banka, Alex Kazior, Cathy Tan, Sabrina Chan, Rumaish Khastgir, Hao Hu, Zakia Youss, Orin Mishkit, Yu-Shin Ding","doi":"10.1039/d4md00866a","DOIUrl":"10.1039/d4md00866a","url":null,"abstract":"PET imaging offers promise for earlier detection and prognostication of Alzheimer's disease. Recently, antibody-based constructs that penetrate the CNS via the transferrin receptor (TfR) have improved tau-selectivity, something that currently limits small molecule tau PET radiotracers. However, it remains unclear if the slow pharmacokinetics of these constructs (MW >50 kDa) limit target binding detection within the time window available for an F-18 based radiotracer. We synthesized three radio-probes by conjugating [18F]SFB with individual bi-specific antibody constructs: 1) a full-size IgG tau antibody conjugated with a TfR fragment (TAUb), 2) a tau-scFv bispecific antibody (TAUs), and 3) an Aβ-scFv bispecific antibody (Aβs). We scanned a series of sex- and age-matched wild-type (WT) and transgenic mice with tauopathy (PS19). Each paired study consisted of three sets of PET/CT scans: an initial low dose dynamic scan followed by two static scans at 8 h and 12 h after injection of a high dose of the same probe. For TAUs probes, the whole brain uptake was higher in PS19 mice (0.0684 ± 0.0273% ID cc-1, n = 5) compared to WT (0.0513 ± 0.0197% ID cc-1, n = 4) though the difference did not reach statistical significance (p = 0.56). Regional quantification analysis provides supporting evidence that TAUs displayed higher specific binding over Aβs in brain regions of PS19 mice. There was net accumulation of all three probes between 8 h and 12 h, suggesting that F-18 radiolabeled bi-specific antibody constructs may not adequately quantitate deposition of tau aggregates within the available time window for F-18, limited by slow pharmacokinetics and lack of a suitable reference region.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11848619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthetic strategies and medicinal chemistry perspectives of dual acting carbonic anhydrase modulators with monoamine oxidase and cholinesterase inhibitors.

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-02-06 DOI: 10.1039/d4md00837e

Sandeep Bindra, Ehab M Mostafa, Mohamed A Abdelgawad, Samy Selim, Sunil Kumar, Bijo Mathew

{"title":"Synthetic strategies and medicinal chemistry perspectives of dual acting carbonic anhydrase modulators with monoamine oxidase and cholinesterase inhibitors.","authors":"Sandeep Bindra, Ehab M Mostafa, Mohamed A Abdelgawad, Samy Selim, Sunil Kumar, Bijo Mathew","doi":"10.1039/d4md00837e","DOIUrl":"10.1039/d4md00837e","url":null,"abstract":"Multi-target drug design (MTDD) represents the paradigm shift in pharmaceutical research, moving beyond the conventional one-drug-one-target approach to address the complexity of multifactorial diseases. This strategy aims to develop single therapeutic candidates that can simultaneously modulate multiple biological targets, offering more comprehensive disease management and reducing the likelihood of drug resistance. In this article, we highlighted the design, synthesis, and structure-activity relationships (SARs) of various dual acting inhibitors involved in treatment of neurodegenerative diseases. Dual acting inhibitors targeting carbonic anhydrases (CAs), monoamine oxidases (MAOs), and cholinesterases (ChEs) have emerged as promising therapeutic agents due to their potential in treating complex neurodegenerative and psychiatric disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). By integrating CA inhibitors with MAO and ChE inhibition, researchers aim to address both the neuroprotective and symptomatic aspects of these disorders. The review also discusses key SAR studies that have guided the optimization of dual inhibitors, focusing on achieving selectivity and potency while minimizing off-target effects. From a medicinal chemistry perspective, the dual inhibition approach offers advantages such as improved efficacy, reduced polypharmacy, and better management of disease progression. However, challenges remain, including maintaining selectivity for target isoforms and overcoming pharmacokinetic limitations. Overall, the development of dual-acting CA-MAO-ChE inhibitors represents a compelling avenue in drug discovery, with the potential to significantly impact the treatment of neurodegenerative diseases.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143383244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Recent progress in emerging molecular targeted therapies for intrahepatic cholangiocarcinoma.

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-02-06 DOI: 10.1039/d4md00881b

Younghoon Kim, Jaewon Song, Namkyoung Kim, Taebo Sim

{"title":"Recent progress in emerging molecular targeted therapies for intrahepatic cholangiocarcinoma.","authors":"Younghoon Kim, Jaewon Song, Namkyoung Kim, Taebo Sim","doi":"10.1039/d4md00881b","DOIUrl":"10.1039/d4md00881b","url":null,"abstract":"Cholangiocarcinoma (CCA) is a diverse group of epithelial malignant tumors arising from the biliary tract, characterized by high molecular heterogeneity. It is classified into intrahepatic (iCCA) and extrahepatic CCA (eCCA) based on the location of the primary tumor. CCA accounts for approximately 15% of all primary liver cancers, with iCCA comprising 10-20% of all CCAs. iCCA is especially known for its characteristic aggressiveness and refractoriness, leading to poor prognosis. Despite the increasing global incidence and mortality rates, surgery remains the only available standard treatment approach for a subset (25%) of patients with early-stage, resectable iCCA. The paucity of effective systemic medical therapies restricts therapeutic options for patients with advanced or metastatic iCCA. In the past decade, advances in the understanding of the molecular complexity of these tumors have provided fruitful insights for the identification of promising new druggable targets and the development of feasible therapeutic strategies that may improve treatment outcomes for patients with iCCA. In this review, we aim to highlight critical up-to-date studies and medicinal chemistry aspects, focusing on novel targeted approaches utilizing promising candidates for molecular targeted therapy in iCCA. These candidates include aberrations in isocitrate dehydrogenase (IDH) 1/2, fibroblast growth factor receptor (FGFR), B-Raf proto-oncogene (BRAF), neurotrophic tyrosine receptor kinase (NTRK), human epidermal growth factor receptor 2 (HER2), and programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1). Furthermore, this review provides an overview of potential inhibitors aimed at overcoming acquired drug resistance in these actionable targets for iCCA.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11800140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143383241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Recent advancements in the development of next-generation dual-targeting antibacterial agents.

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-02-05 DOI: 10.1039/d4md00934g

Firdoos Ahmad Sofi, Mayank, Mubashir H Masoodi, Nahida Tabassum

引用次数: 0

Simple accessible clemastine fumarate analogues as effective antileishmanials.

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-01-31 DOI: 10.1039/d4md01004c

Rebecca L Charlton, Douglas O Escrivani, Christopher Brown, Niranjan Thota, Victor S Agostino, Exequiel O J Porta, Timur Avkiran, Andrew T Merritt, Paul W Denny, Bartira Rossi-Bergmann, Patrick G Steel

引用次数: 0