RSC medicinal chemistry最新文献_第5页

AlbiCDN: albumin-binding amphiphilic STING agonists augment the immune activity for cancer immunotherapy† AlbiCDN：结合白蛋白的两亲性STING激动剂增强肿瘤免疫治疗的免疫活性。

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 and 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 and 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":" 4","pages":" 1797-1807"},"PeriodicalIF":4.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Site-specific molecular glues for the 14-3-3/Tau pS214 protein-protein interaction via reversible covalent imine tethering. 14-3-3/Tau pS214蛋白通过可逆共价亚胺系聚作用的位点特异性分子胶。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-02-07 DOI: 10.1039/d4md00833b

Ansgar Oberheide, Maxime C M van den Oetelaar, Jakob J A Scheele, Jan Borggräfe, Semmy F H Engelen, Michael Sattler, Christian Ottmann, Peter J Cossar, Luc Brunsveld

{"title":"Site-specific molecular glues for the 14-3-3/Tau pS214 protein-protein interaction via reversible covalent imine tethering.","authors":"Ansgar Oberheide, Maxime C M van den Oetelaar, Jakob J A Scheele, Jan Borggräfe, Semmy F H Engelen, Michael Sattler, Christian Ottmann, Peter J Cossar, Luc Brunsveld","doi":"10.1039/d4md00833b","DOIUrl":"10.1039/d4md00833b","url":null,"abstract":"Protein-protein interactions (PPIs) are key regulators of various cellular processes. Modulating PPIs with small molecules has gained increasing attention in drug discovery, particularly targeting the 14-3-3 protein family, which interacts with several hundred client proteins and plays a central role in cellular networks. However, targeting a specific PPI of the hub protein 14-3-3, with its plethora of potential client proteins, poses a significant selectivity challenge. This not only involves the selectivity of 14-3-3 PPIs with other client proteins, but also the selective stabilization of a specific 14-3-3 binding site within a protein partner featuring several binding sites. The interaction of 14-3-3 with Tau, characterized by different phospho-site driven binding modes, forms a valuable, disease-relevant, 14-3-3 multivalent model PPI to explore this selectivity issue. This work presents the identification and early-stage optimization of small molecule fragment-like stabilizers for a specific binding site of the 14-3-3/Tau PPI. Using different biophysical assays, the stabilizing potency of the imine-bond forming molecules was mapped and X-ray crystallography studies provided structural data on the binding mode of the ternary complexes. Exploiting the unique topologies and functionalities of the different binding sites enabled the engineering of selectivity for this initial molecular glue matter for the pS214 binding site, over a second 14-3-3 binding site in Tau (pS324). These reversible covalent tool compounds will allow for the further exploration of the role of 14-3-3 in Tau aggregation.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606224","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

Synthesis of fluorinated tubastatin A derivatives with bi-, tri-, and tetracyclic cap groups: molecular docking with HDAC6 and evaluation of in vitro antitumor activity. 双环、三环和四环帽基氟化管伐他汀A衍生物的合成：与HDAC6的分子对接及体外抗肿瘤活性评价

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 and 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 and 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":" 4","pages":" 1808-1817"},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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 单胺氧化酶和胆碱酯酶抑制剂双作用碳酸酐酶调节剂的合成策略及药物化学前景。

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 and 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 and 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":" 4","pages":" 1532-1549"},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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. 肝内胆管癌分子靶向治疗新进展。

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. 新一代双靶向抗菌药物的研究进展。

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

The synthesis and investigation of novel 3-benzoylbenzofurans and pyrazole derivatives for anti-HIV activity. 新型3-苯甲酰苯并呋喃及吡唑类抗hiv活性衍生物的合成与研究。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-02-05 DOI: 10.1039/d4md00844h

Sinothile S Khuzwayo, Mamoalosi A Selepe, Debra Meyer, Ntombenhle H Gama

{"title":"The synthesis and investigation of novel 3-benzoylbenzofurans and pyrazole derivatives for anti-HIV activity.","authors":"Sinothile S Khuzwayo, Mamoalosi A Selepe, Debra Meyer, Ntombenhle H Gama","doi":"10.1039/d4md00844h","DOIUrl":"10.1039/d4md00844h","url":null,"abstract":"The emergence of drug-resistant viruses continues to be an obstacle to effectively controlling the HIV/AIDS pandemic. The development of novel drugs with high potency and the ability to fully eradicate HIV-1 infections is therefore of critical importance. Novel pyrazole derivatives were synthesized from 3-benzoylbenzofurans and characterized by mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. The 3-benzoyl benzofurans were determined to be highly cytotoxic in TZM-bl cells, while their pyrazole derivatives were mild to non-cytotoxic. Evaluation of anti-HIV activities in pseudoviruses revealed two 3-benzoyl benzofurans (3g and 4b) and pyrazoles (5f and 5h) as the most potent inhibitors. The IC50 values of 4b and 5f were 0.49 ± 0.11 μM and 0.39 ± 0.13 μM in Q23 and 0.12 ± 0.05 μM and 1.00 ± 0.15 μM in the CAP210 pseudovirus, respectively. Further evaluations for mechanism of action involved the time of addition assay and direct enzyme inhibition, which showed that 3g and 4b were non-nucleotide reverse transcriptase inhibitors while 5f and 5h inhibited HIV entry. Additionally, 3g, 4b, and 5h were found to be mild inhibitors of HIV-1 protease, while 5f was the most active protease inhibitor. The IC50 value of 5f was 31.59 ± 3.83 μM, and it displayed interactions with the active site of HIV-1 PR, suggesting competitive inhibition using molecular docking. The promising anti-HIV activities of 5f in pseudoviruses and HIV-PR motivate its further development for antiretroviral drugs.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11883425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586545","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

PK 11195 derivatives: exploring the influence of amide and heterocyclic substitution on A147T TSPO discrimination. PK 11195衍生物：探索酰胺和杂环取代对A147T TSPO辨别的影响。

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-02-04 DOI: 10.1039/d4md00798k

Renee Sokias, Andrea Zhao, Eryn L Werry, Andrew P Montgomery, David E Hibbs, Michael A Sullivan, André D J McKenzie, Grace A Cumbers, Beau M Allen, Jonathan J Danon, Michael Kassiou

{"title":"PK 11195 derivatives: exploring the influence of amide and heterocyclic substitution on A147T TSPO discrimination.","authors":"Renee Sokias, Andrea Zhao, Eryn L Werry, Andrew P Montgomery, David E Hibbs, Michael A Sullivan, André D J McKenzie, Grace A Cumbers, Beau M Allen, Jonathan J Danon, Michael Kassiou","doi":"10.1039/d4md00798k","DOIUrl":"10.1039/d4md00798k","url":null,"abstract":"The translocator protein (TSPO) is an 18 kDa protein on the outer mitochondrial membrane. It has gained significant interest in recent years for its potential as a therapeutic target and imaging biomarker, particularly in neuroinflammation, cancer, and central nervous system disorders (CNS). Clinical translation of ligands has been complicated by the presence of a common single nucleotide polymorphism (A147T TSPO), at which many disclosed TSPO ligands lose affinity. One exception is the first-generation TSPO ligand PK 11195, however, this ligand possesses unfavourable pharmacokinetic properties limiting translation in CNS applications. We aimed to investigate which motifs of this ligand contribute to high binding at the wild type (WT) and A147T TSPO isoforms with the aim of identifying elements that may tolerate lipophilicity-reducing substitutions. Affinities for a small library of isoquinoline, quinazoline, indole and azaindole carboxamides with varying aliphatic and aromatic substituents were measured using radioligand binding at both TSPO isoforms, with computational studies performed to rationalise the experimentally measured binding. The heterocycle and acetamide substituents of PK 11195 were found to play a role in its non-discriminating nature. In addition, the study yielded 2a, a high affinity, non-discriminating TSPO ligand. Modelling suggests its high affinity and lack of discrimination results from additional π-π interactions introduced at the binding site of both TSPO isoforms. These findings provide a foundation for developing TSPO ligands with improved clinical properties and insensitivity to A147T polymorphism.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11883422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586544","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

Design, synthesis and evaluation of pyrimidinobenzylamide and pyrimidinothiophenamide derivatives as inhibitors of DOT1L and related epigenetic targets DNMT3a, PRMT4 and other HMTs. 作为DOT1L及相关表观遗传靶点DNMT3a、PRMT4等hmt抑制剂的嘧啶氨基苄胺和嘧啶氨基噻吩酰胺衍生物的设计、合成和评价

IF 4.1 4区医学

RSC medicinal chemistry Pub Date : 2025-01-30 DOI: 10.1039/d4md00899e

Oscar Omar Castillo-Aguilera, Patrick Depreux, Ludovic Halby, Christian Bailly, Lenin Domínguez-Ramírez, Sheraz Gul, Paola B Arimondo, Laurence Goossens

{"title":"Design, synthesis and evaluation of pyrimidinobenzylamide and pyrimidinothiophenamide derivatives as inhibitors of DOT1L and related epigenetic targets DNMT3a, PRMT4 and other HMTs.","authors":"Oscar Omar Castillo-Aguilera, Patrick Depreux, Ludovic Halby, Christian Bailly, Lenin Domínguez-Ramírez, Sheraz Gul, Paola B Arimondo, Laurence Goossens","doi":"10.1039/d4md00899e","DOIUrl":"10.1039/d4md00899e","url":null,"abstract":"The histone methyltransferase DOT1L (DOT1 like, disruptor of telomeric silencing) is responsible for methylation of H3K79, leading to oncogene transcription, and it is involved in the development of different types of cancers such as MLL-rearranged leukemia (MLL-r, myeloid-lymphoid leukemia). Inhibitors of DOT1L have therapeutic potential. Thus, we present herein the in silico based design and the multi-step synthesis of different series of non-nucleosidic compounds that mimic the S-adenosyl-l-methionine (SAM) cofactor and inhibit DOT1L. The compounds incorporate an aminopyrimidine moiety coupled to a functionalized aryl based on the structure of published DOT1L inhibitors that have entered clinical trials (EPZ-5676, pinometostat). Their DOT1L activity was determined and structure-activity relationships (SARs) were established, leading to the identification of key moieties for the development of DOT1L-selective compounds. To determine their specificity, the activity of the compounds was evaluated on other methyltransferases that also use SAM as a cofactor, such as DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs), including the PRC2 complex, G9a, PRMT1, PRMT4 and PRMT5. We identified compound 19d (IC50 = 8.0 μM) as a DNMT3a inhibitor, and 1n (EC50 = 19.0 μM), 1p (EC50 = 4.8 μM) and 19g (EC50 = 11.0 μM) as PRMT4 inhibitors based on the in silico approach that was employed. The in vitro ADMET profile of the compounds matched with the generally accepted lead-like criteria and encouraged the further optimization of these non-nucleosidic hit compounds.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11886420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586541","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