Journal of Medicinal Chemistry最新文献_第4页

Efficient Silencing of Androgen Receptor Gene via UTR-Targeting siRNAs for Androgenetic Alopecia Therapy. 通过utr靶向sirna有效沉默雄激素受体基因治疗雄激素性脱发。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-26 DOI: 10.1021/acs.jmedchem.5c01739

Di Feng,Xinli Fan,Yuqiang Hu,Yizhi Man,Qian Wang,Yanmin Song,Jingjing Zhou,Jin Zhang,Yun Luo,Jing Wang,Xinjing Tang

{"title":"Efficient Silencing of Androgen Receptor Gene via UTR-Targeting siRNAs for Androgenetic Alopecia Therapy.","authors":"Di Feng,Xinli Fan,Yuqiang Hu,Yizhi Man,Qian Wang,Yanmin Song,Jingjing Zhou,Jin Zhang,Yun Luo,Jing Wang,Xinjing Tang","doi":"10.1021/acs.jmedchem.5c01739","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01739","url":null,"abstract":"Androgenetic alopecia (AGA) is predominantly driven by excessive local activity of dihydrotestosterone (DHT), leading to follicular miniaturization and progressive hair loss. The need for novel treatment strategies for AGA is emphasized by the side effects and postoperative sequelae of current therapeutic approaches, including pharmacological interventions and surgical procedures. Small-interfering RNAs (siRNAs) have emerged as promising therapeutic candidates due to their target specificity, the enhanced efficacy, and long-term effect. Here, we screened a series of siRNA sequences targeting non-coding region of androgen receptor (AR) gene and identified a lead siRNA candidate (AR-27) conserved betweenHomo sapiens andMus musculus. The chemically modified and cholesterol-conjugated candidate (AR-27 E-Chol) was evaluated in both cells and DHT-induced AGA mice model. AR-27 E-Chol effectively stimulated dorsal hair regrowth and significantly downregulated AR gene expression in skin tissues. These findings support the clinical potential of AR-27 E-Chol as an effective therapeutic candidate for AGA.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"42 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Mitochondria-Targeting 1H-Imidazo[4,5-f][1,10]phenanthroline-Based Binuclear Ru(II)/Ir(III)/Re(I) Complexes as a Promising Avenue for In Vitro Genotoxicity and In Vivo Tumor Immunotherapy. 线粒体靶向1h -咪唑[4,5-f][1,10]邻菲罗啉双核Ru(II)/Ir(III)/Re(I)复合物作为体外遗传毒性和体内肿瘤免疫治疗的有前景的途径。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-25 DOI: 10.1021/acs.jmedchem.5c00523

Binoy Kar,Ashikur Rahaman,Maynak Pal,Ankur Banerjee,Mithun Roy,Rinku Chakrabarty,Shamee Bhattacharjee,Deba Prasad Mandal,Priyankar Paira

{"title":"Mitochondria-Targeting 1H-Imidazo[4,5-f][1,10]phenanthroline-Based Binuclear Ru(II)/Ir(III)/Re(I) Complexes as a Promising Avenue for In Vitro Genotoxicity and In Vivo Tumor Immunotherapy.","authors":"Binoy Kar,Ashikur Rahaman,Maynak Pal,Ankur Banerjee,Mithun Roy,Rinku Chakrabarty,Shamee Bhattacharjee,Deba Prasad Mandal,Priyankar Paira","doi":"10.1021/acs.jmedchem.5c00523","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00523","url":null,"abstract":"Bimetallic complexes have recently emerged as a promising tool for synergistic photodynamic therapy and chemotherapy in oncology. However, the effectiveness of existing therapies remains limited in the treatment of triple-negative breast cancer (MDA-MB-231) and human melanoma cancer (A375). In this study, we introduced mitochondrial-targeting imidazophenanthroline-based binuclear Ru(II)/Ir(III)/Re(I) complexes capable of generating ROS, facilitating mitochondrial dysfunction and oxidative DNA damage, and inducing G0/G1 phase cell cycle arrest. Among all these complexes, the naphthalene-substituted imidazophenanthroline-based bisiridium complex (BNS-2) exhibited the best potency against MDA-MB-231 TNBC and A375 cancer cell lines. Eventually, this complex induced the upregulation of BAX and cleaved caspase-3, downregulated BCL-2, triggered the caspase 3/9 pathway for apoptosis, and shifted the death mechanism from necrosis to apoptosis in tumor cells in vivo. This complex significantly reduced tumor volume and protected the mice against significant weight loss without causing liver or kidney toxicity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"100 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Discovery of CaSR Peptide Agonists via Multistage Screening: In Silico Design, In Vitro Validation, and In Vivo Efficacy 通过多阶段筛选发现CaSR肽激动剂：计算机设计、体外验证和体内疗效

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-25 DOI: 10.1021/acs.jmedchem.5c01119

Yu Yuan, Yuqing Guan, Lin Zhou, Bo Huang, Haixia Liu, Xiaobin Qin, Xuan Tang, Guangpeng Xue, Binbin Xu, Yinghao Pan, Xiaomin Liu, Zhen Shi, Lan Zhang, Guangpeng Meng, Yuanbo Li

{"title":"Discovery of CaSR Peptide Agonists via Multistage Screening: In Silico Design, In Vitro Validation, and In Vivo Efficacy","authors":"Yu Yuan, Yuqing Guan, Lin Zhou, Bo Huang, Haixia Liu, Xiaobin Qin, Xuan Tang, Guangpeng Xue, Binbin Xu, Yinghao Pan, Xiaomin Liu, Zhen Shi, Lan Zhang, Guangpeng Meng, Yuanbo Li","doi":"10.1021/acs.jmedchem.5c01119","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01119","url":null,"abstract":"Human calcium-sensing receptor (CaSR) is a class C G protein–coupled receptor (GPCR) that directly regulates parathyroid hormone release and maintains calcium homeostasis. The discovery of potent CaSR agonists with computer-aided drug design (CADD) has been appealing. Herein, we report the discovery of a series of new CaSR agonists by enhancing the molecular binding affinity through the replacement of key residues via the iCVETide platform. Ac-D-Cys(L-Cys)-D-Arg-D-(3-Gu)-Phe-D-Abu-D-Arg-D-Ala-D-Arg-NH2 (compound 6g) with an outstanding activity and a satisfactory ADME profile is discovered, and the interaction mode between 6g and CaSR is elucidated through molecular docking and molecular dynamics simulations, showing hydrogen bonds, salt bridges, and π–π stacking. In addition, 6g is capable of activating human CaSR as a calcimimetic positive allosteric modulator. Our results provide a viable alternative to approved calcimimetics and a novel protocol for the discovery of CaSR agonists.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"95 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Old Dog, New Tricks: Ibogaine and Its Analogs as Potential Neurotherapeutics 老狗，新把戏：伊博格因及其类似物作为潜在的神经治疗药物

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-25 DOI: 10.1021/acs.jmedchem.5c02510

Saghir Ali, , , Xiaochen Tian, , , Kathryn A. Cunningham*, , and , Jia Zhou*,

引用次数: 0

A Broad-Spectrum Abietane Diterpenoid Derivative that Targets Lipid II Cycle and Bacterial Membrane to Combat Multidrug Resistance 针对脂质II周期和细菌膜对抗多药耐药的广谱阿比烷二萜衍生物

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-25 DOI: 10.1021/acs.jmedchem.5c01657

Yajing Li, Ziqi Yin, Shuhui Liu, Xiaolei Bian, Zhifu Chen, Zhiwei Ren, Dianyan Chen, Xiaomei Fu, Jinyong Zhang, Xinxin Feng, Dongliang Guan

{"title":"A Broad-Spectrum Abietane Diterpenoid Derivative that Targets Lipid II Cycle and Bacterial Membrane to Combat Multidrug Resistance","authors":"Yajing Li, Ziqi Yin, Shuhui Liu, Xiaolei Bian, Zhifu Chen, Zhiwei Ren, Dianyan Chen, Xiaomei Fu, Jinyong Zhang, Xinxin Feng, Dongliang Guan","doi":"10.1021/acs.jmedchem.5c01657","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01657","url":null,"abstract":"The escalating threat of drug-resistant superbugs has urgently necessitated the development of antibiotics with novel scaffolds and mechanisms. Herein, we rationally designed and synthesized novel abietane diterpenoid derivatives from carnosic acid (CA) inspired by the “amine/guanidine” modification strategy. Most derivatives designed exhibited greater activities than CA and even vancomycin (∼2–64-fold). The optimized 4c demonstrated ultrabroad-spectrum activity against MRSA, VRE, CRAB, and mycobacteria, coupled with desirable properties of rapid bactericidal ability, low resistance development propensity, and good safety profile. Mechanistic studies first revealed a novel independent and synergistic “cell wall–membrane” dual inhibitory mechanism, respectively, via interfering with bacterial lipid II cycle and inducing membrane permeabilization and depolarization. Subsequent in vivo studies elucidated that 4c demonstrated favorable efficacy in zebrafish and mouse infection models. Collectively, these findings highlight the antimicrobial potential of abietane diterpenoids derived from CA and identify 4c as a promising drug candidate against drug-resistant bacterial infections.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Application of Weighted Interaction-Fingerprints for Rationalizing Neosubstrate Potency and Selectivity of Cereblon-Based Molecular Glues 加权相互作用指纹图谱在小脑基分子胶新底物效价和选择性评价中的应用

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-25 DOI: 10.1021/acs.jmedchem.5c01919

Guilian Luchini, Shuang Liu, Hannah L. Powers, Emily Cherney, Jinyi Zhu, Kristina Danga, Joel W. Thompson, Lihong Shi, Barbra Pagarigan, Dong Donna Wei, Peter Park, Andrew P. Degnan, Christoph W. Zapf, Jennifer R. Riggs, Scott Johnson, Thomas Cummins

{"title":"Application of Weighted Interaction-Fingerprints for Rationalizing Neosubstrate Potency and Selectivity of Cereblon-Based Molecular Glues","authors":"Guilian Luchini, Shuang Liu, Hannah L. Powers, Emily Cherney, Jinyi Zhu, Kristina Danga, Joel W. Thompson, Lihong Shi, Barbra Pagarigan, Dong Donna Wei, Peter Park, Andrew P. Degnan, Christoph W. Zapf, Jennifer R. Riggs, Scott Johnson, Thomas Cummins","doi":"10.1021/acs.jmedchem.5c01919","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01919","url":null,"abstract":"Cullin-RING Ligase 4 Cereblon (CRL4CRBN) (CRBN) E3 ligase modulatory drugs (CELMoDsTM) make up a successful class of compounds targeting neosubstrates for proteasome-dependent degradation. Early immunomodulatory drugs (IMiDsTM) target Ikaros and Aiolos degradation. In addition, there are ongoing clinical trials targeting the degradation of biologically relevant proteins such as GSPT1, CK1α, and Helios with CRBN-based molecular glues. To date, most advanced preclinical and clinical CRBN-based molecular glues recruit their neosubstrates through canonical G-motifs, secondary protein features that are structurally similar but have significantly different amino acid sequence identities. Analogous to the development of kinase inhibitors, optimizing both neosubstrate recruitment and degradation selectivity is important to minimize potential off-target activity. Here, we describe a computational structure-based approach to analyze and predict putative ligand interactions important in the neosubstrate ternary complex. This approach provides valuable insights for enhanced designs toward the development of more selective and efficacious CRBN-based molecular glues.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"40 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Proposed Cuts to Health Research Threaten the Future of Drug Discovery and Development 削减健康研究经费的提议威胁到药物发现和开发的未来

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-25 DOI: 10.1021/acs.jmedchem.5c02080

David E. Heppner,

引用次数: 0

Discovery of Potent and Selective Reversible Ubiquitin-Like Modifier Activating Enzyme 5 Inhibitors Targeting the UFMylation Pathway 靶向ufmy化途径的有效和选择性可逆泛素样修饰剂激活酶5抑制剂的发现

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-25 DOI: 10.1021/acs.jmedchem.5c02305

James J. Mignone, Elizabeth A. Jurica, Deepa Rajasekaran, Jaclyn Robustelli, Courtney McCarthy, Phong Q. Quang, Qi Guo, Darby J. Ball, Andrew F. Donnell, Brian P. Mahon, Dawn Mulligan, Steven A. Spronk, Shivangi Srivastava, Erik C. Vik, Cullen L. Cavallaro, Farya J. Chattergoon, Bruce A. Ellsworth, Shriya Joshi, Emma Lees, R. Michael Lawrence, Ling Li, Selyna Mai, Mohammad K. Manik, Frank Marsilio, Konstantinos Mavrakis, Paramasivam Murugan, John A. Newitt, Payal Sheth, Jeffrey Tredup, Sarah C. Traeger, David D. Weis, Chunhong Yan, Joseph Yanchunas, Jr., Ping Zhang, Stephen T. Wrobleski, Peter Kalev, Joanne J. Bronson

{"title":"Discovery of Potent and Selective Reversible Ubiquitin-Like Modifier Activating Enzyme 5 Inhibitors Targeting the UFMylation Pathway","authors":"James J. Mignone, Elizabeth A. Jurica, Deepa Rajasekaran, Jaclyn Robustelli, Courtney McCarthy, Phong Q. Quang, Qi Guo, Darby J. Ball, Andrew F. Donnell, Brian P. Mahon, Dawn Mulligan, Steven A. Spronk, Shivangi Srivastava, Erik C. Vik, Cullen L. Cavallaro, Farya J. Chattergoon, Bruce A. Ellsworth, Shriya Joshi, Emma Lees, R. Michael Lawrence, Ling Li, Selyna Mai, Mohammad K. Manik, Frank Marsilio, Konstantinos Mavrakis, Paramasivam Murugan, John A. Newitt, Payal Sheth, Jeffrey Tredup, Sarah C. Traeger, David D. Weis, Chunhong Yan, Joseph Yanchunas, Jr., Ping Zhang, Stephen T. Wrobleski, Peter Kalev, Joanne J. Bronson","doi":"10.1021/acs.jmedchem.5c02305","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02305","url":null,"abstract":"Ubiquitin-like modifier activating enzyme 5 (UBA5), an E1 enzyme in the UFMylation pathway, is of interest as a therapeutic target in diseases such as cancer due to the critical role that UFMylation plays in cellular function. Strategic structure–activity relationship optimization of high-throughput screen hit 6, a Bruton’s tyrosine kinase covalent inhibitor, was conducted by using both conventional and microscale library synthesis. This approach identified 49 and 50 as potent and selective noncovalent UBA5 inhibitors with significantly improved surface plasmon resonance and nanodifferential scanning fluorimetry biophysical profiles. Cellular target engagement for 49 and 50 was confirmed by a cellular thermal shift assay and translated to inhibition of UFMylation of UBA5 and UFC1 in retinal pigment epithelial-1 cells as well as reduction of UFMylation of the downstream protein UFMylation substrate RPL26. Furthermore, 49 and 50 demonstrated specificity for UBA5 among the other E1–E2 transesterification pathways. In this communication, we report the discovery and synthesis of potent and selective UBA5 inhibitors, providing valuable tool compounds for studying the UFMylation pathway.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Dual Transcriptional Repression of Oncogenic c-KIT and KRAS by G4-Targeting Triazolyl-Indole Scaffolds Induces Synthetic Lethality in Leukemia Cells. g4靶向三唑吲哚支架对致癌c-KIT和KRAS的双重转录抑制诱导白血病细胞的合成致死

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-25 DOI: 10.1021/acs.jmedchem.5c00736

Tathagato Bhattacharyya,Sarmistha Pal,Sayantan Pradhan,Jyotirmayee Dash

引用次数: 0

Resolving Enzyme–Substrate–Activator Ambiguity: A Minimalist Enzyme Kinetic Framework for PROTAC Design and Optimization 解决酶-底物-活化剂的歧义：用于PROTAC设计和优化的极简酶动力学框架

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-09-25 DOI: 10.1021/acs.jmedchem.5c02374

Bharath Srinivasan*,

引用次数: 0