Journal of Medicinal Chemistry最新文献

High-Affinity Probes for Androgen Receptor Imaging: From Cells and In Silico Modeling to Whole-Body Fluorescent Applications. 高亲和探针雄激素受体成像：从细胞和硅建模到全身荧光应用。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-07-25 DOI: 10.1021/acs.jmedchem.5c00836

Saheed A Ayodeji,Yaroslav Balytskyi,Destina Unaegbu,Allison Ingman,Christopher V Kelly,Sheryl Roberts

{"title":"High-Affinity Probes for Androgen Receptor Imaging: From Cells and In Silico Modeling to Whole-Body Fluorescent Applications.","authors":"Saheed A Ayodeji,Yaroslav Balytskyi,Destina Unaegbu,Allison Ingman,Christopher V Kelly,Sheryl Roberts","doi":"10.1021/acs.jmedchem.5c00836","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00836","url":null,"abstract":"Castrate-resistant prostate cancer (CRPC) is driven by androgen receptor (AR) signaling. Imaging tools to monitor AR signaling dynamics are a high-priority goal. Here, we introduce ARi-FL, a series of visible- and near-infrared fluorescent AR inhibitors. Based on an aryloxy cyclohexane scaffold, a neolinker enabled amine-based conjugation to fluorophores. ARi-FL showed potent AR inhibition (IC50 ∼ 13 nM) and allowed visualization of cytoplasmic AR, correlating with AR-expressing cells, which were blockable with excess unlabeled ligand. In vivo and ex vivo studies in human prostate cancer models confirmed ARi-FL localization in AR-positive tumors. In silico modeling across wild-type (WT) and clinically relevant AR mutants (F877L, T878A, H875Y, W742C, and F877L/T878A) revealed nanomolar binding affinities (Kd ∼ 1-2 nM), consistent with experimental results. ARi-FL probes demonstrated high selectivity, practical yields, and stability. Taken together, ARi-FL offers a chemical imaging platform for noninvasive AR tracking with applications for studying resistance mechanisms of AR and guiding treatment decisions.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"25 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701267","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

Identification of 5,7-Dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one Derivatives as ENPP1 Inhibitors for STING Pathway-Mediated Immunotherapy. 5,7-二氢- 6h -吡咯[2,3-d]嘧啶-6- 1衍生物在STING途径介导的免疫治疗中作为ENPP1抑制剂的鉴定

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-07-25 DOI: 10.1021/acs.jmedchem.5c01021

Su Hyun Ji,Miso Kang,Hyomin Ahn,Soo Yeon Baek,In-Gyun Lee,Hanul Jeon,Hwan Won Chung,Dong Kyun Han,Seoyeong Yang,Hyebin Lee,Yeseul Kim,Ji Hun Wi,Jeehee Lee,Younghun Yoo,Sungbae Kang,Mihue Jang,Byungsun Jeon,Nam-Jung Kim,Chiman Song,Sanghee Lee,Seo-Jung Han

引用次数: 0

Structure-Activity Relationship Guided Scaffold Hopping Resulted in the Identification of GLPG4970, a Highly Potent Dual SIK2/SIK3 Inhibitor. 结构-活性关系引导的支架跳跃导致GLPG4970的鉴定，这是一种高效的SIK2/SIK3双抑制剂。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-07-25 DOI: 10.1021/acs.jmedchem.5c01401

Hans Kelgtermans,Maxim De Wachter,Stijn Heyndrickx,Sandy El Bkassiny,Tatiana Lacarriere,Chris Laruelle,Jörg Heiermann,Wendy van Bruggen,Katarzyna Drabik,Denis Bucher,Thomas Coudrat,Emilie Jigorel,Kenneth Goossens,Michael Drennan,Martine Vrints,Maarten Verbeeck,Bas Housmans,Damien Ronsse,David Moreno-Delgado,Vahid Nassiri,Mia Jans,Maarten Gees,Emanuelle Wakselman,Line Oste,Monica Borgonovi,Elena Borregán-Ochando,Vladyslav Sushko,Alain Monjardet,Camille Dusserre,Frederique Van Acker,Anouk Blaauw,Stephanie Lavazais,Catherine Jagerschmidt,Didier Merciris,Michael Török-Schafroth,Christian A Seemayer,Katja Conrath,Fabrice A Kolb,Pierre Raboisson,Reginald Brys,David Amantini,Romain Gosmini,Alexis Denis,Juan-Miguel Jimenez,Steve De Vos,Nicolas Desroy

{"title":"Structure-Activity Relationship Guided Scaffold Hopping Resulted in the Identification of GLPG4970, a Highly Potent Dual SIK2/SIK3 Inhibitor.","authors":"Hans Kelgtermans,Maxim De Wachter,Stijn Heyndrickx,Sandy El Bkassiny,Tatiana Lacarriere,Chris Laruelle,Jörg Heiermann,Wendy van Bruggen,Katarzyna Drabik,Denis Bucher,Thomas Coudrat,Emilie Jigorel,Kenneth Goossens,Michael Drennan,Martine Vrints,Maarten Verbeeck,Bas Housmans,Damien Ronsse,David Moreno-Delgado,Vahid Nassiri,Mia Jans,Maarten Gees,Emanuelle Wakselman,Line Oste,Monica Borgonovi,Elena Borregán-Ochando,Vladyslav Sushko,Alain Monjardet,Camille Dusserre,Frederique Van Acker,Anouk Blaauw,Stephanie Lavazais,Catherine Jagerschmidt,Didier Merciris,Michael Török-Schafroth,Christian A Seemayer,Katja Conrath,Fabrice A Kolb,Pierre Raboisson,Reginald Brys,David Amantini,Romain Gosmini,Alexis Denis,Juan-Miguel Jimenez,Steve De Vos,Nicolas Desroy","doi":"10.1021/acs.jmedchem.5c01401","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01401","url":null,"abstract":"Inhibition of salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 represents a new potential therapeutic approach for autoimmune and inflammatory disease treatment via modulation of pro-inflammatory and immunoregulatory pathways, particularly inhibition of SIK2 and SIK3. After discovering a new chemotype for SIK inhibition, further optimization of potency, selectivity, ADMET and PK properties resulted in a 1,6-naphtyridine containing molecule GLPG4876 (7). However, 7 was clastogenic when examined in vivo in rat micronucleus assays, preventing further development. Overlay of 7 with GLPG3970 (6) within the SIK3 protein structure inspired the design of pyridine derivatives, leading to the identification of GLPG4970 (8). Compound 8 was negative in genotoxicity screening assays and demonstrated potent SIK2/SIK3 inhibition, for which isoform selectivity was determined in a cellular context. Compound 8 displayed improved potency compared with previously reported SIK inhibitors in biochemical and phenotypic cellular assays, and showed dose-dependent activity in disease relevant mouse pharmacological models of colitis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"704 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701266","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 BI-2493, a Pan-KRAS Inhibitor Showing In Vivo Efficacy. 具有体内疗效的泛kras抑制剂BI-2493的发现。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-07-25 DOI: 10.1021/acs.jmedchem.5c00576

Joachim Bröker,Alex G Waterson,Timothy R Hodges,Jason R Abbott,Allison Arnold,Jark Böttcher,Nina Braun,Jianwen Cui,Julian E Fuchs,Thomas Gerstberger,Sebastian Gogg,Sabine Hanner,Lorenz Herdeis,Lucas W Howell,Andreas Mantoulidis,Moriz Mayer,Jason Phan,Francesca Rocchetti,Kyra Sankar,Dhruba Sarkar,Otmar Schaaf,John L Sensintaffar,Qi Sun,Tobias Wunberg,Stephen W Fesik

引用次数: 0

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-07-24

Changkai Jia, Pengli Wei, Shiyang Sun, Yaqiu Mao, Ting Wei, Zhenze Qi, Fan Feng, Yalei Wang, Xu Cai, Zhiyuan Zhao, Bingkun Li, Min Qiao, Yaxin Zou, Ziyun Zhang, Tingting Yang, Xiaomei Zhuang*, Junhai Xiao*, Xuesong Feng*, Pengyun Li*, Zhibing Zheng* and Song Li,

引用次数: 0

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-07-24

Zulma Santisteban Valencia, Jennifer Kingston, Filip Miljković, Hannah Rowbottom, Nadia Mann, Sophie Davies, Martin Ekblad, Silvio Di Castro, Karolina Kwapień, Erik Malmerberg, Stig D. Friis, Thomas Lundbäck*, Tomas Leek* and Johan Wernevik*,

引用次数: 0

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-07-24

Rajamanikkam Kamaraj, Ivana Mejdrová, Maria Krutakova, Tomas Smutny, Kryštof Škach, Klara Dohnalova, Lucie Smutna, Dharani Sai Sreekanth Nellore, Jan Dusek, Karel Chalupsky, Jana Hricová, Thales Kronenberger, Aaron Stahl, Markus Templin, Albert Braeuning, Radim Nencka* and Petr Pavek*,

引用次数: 0

Overcoming E3 Ligase-Mediated Resistance: Development of Novel Hydrophobic Tagging-Based Degraders Targeting ALK Protein. 克服E3连接酶介导的抗性：开发新的基于疏水标记的ALK蛋白降解物。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-07-24 DOI: 10.1021/acs.jmedchem.5c00488

Shaowen Xie,Jingjie Zhu,Fangyi Zhan,Dazhi Feng,Chen He,Lihua Liu,Jia Xie,Jingyu Liu,Ming Zhong,Xingting Zhang,Jinyi Xu,Hong Yao,Shengtao Xu

{"title":"Overcoming E3 Ligase-Mediated Resistance: Development of Novel Hydrophobic Tagging-Based Degraders Targeting ALK Protein.","authors":"Shaowen Xie,Jingjie Zhu,Fangyi Zhan,Dazhi Feng,Chen He,Lihua Liu,Jia Xie,Jingyu Liu,Ming Zhong,Xingting Zhang,Jinyi Xu,Hong Yao,Shengtao Xu","doi":"10.1021/acs.jmedchem.5c00488","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00488","url":null,"abstract":"Traditional PROTACs, despite their groundbreaking role in targeted protein degradation (TPD), rely on E3 ubiquitin ligases and are vulnerable to resistance. In this study, we discovered norbornene- and bornane-based hydrophobic tags (HyTs) that efficiently degrade anaplastic lymphoma kinase (ALK). Notably, a novel hydrophobic tag, bornane was first identified. Both norbornene-based HyT J26 and bornane-based HyT J21 demonstrated significant degradation and antiproliferative activity in vitro. J26 achieves effective degradation of the EML4-ALK fusion protein in H3122 cells with CRBN expression knocked down via siRNA. In vivo, J26 significantly suppresses tumor growth with moderate oral bioavailability. Remarkably, J26 effectively targets ALK through the Hsp70 chaperone system and the ubiquitin-proteasome pathway, by passing the need for E3 ligase CRBN. This feature addresses a potential resistance mechanism arising from E3 ligase downregulation, thereby enhancing the potential of HyT technology in precision oncology.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693346","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

Solvent-Free procedure of an A9 Peptide Dimer Exhibiting Specific HER2 Receptor Binding: Fluorescence Spectroscopy Evaluation of the Enhanced Binding Affinity. 具有特异性HER2受体结合的A9肽二聚体的无溶剂过程：荧光光谱评价增强的结合亲和力。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-07-24 DOI: 10.1021/acs.jmedchem.5c01194

Valentina Verdoliva,Giuseppe Digilio,Emanuela Iaccarino,Stefania De Luca

引用次数: 0

SAR-Guided Development of Small-Molecule SERCA2a Activators: Discovery of Potent Indoline, Benzofuran, and Benzodioxole Analogs for Cardiovascular Applications. sar引导下小分子SERCA2a激活剂的开发：发现用于心血管应用的强效吲哚、苯并呋喃和苯二唑类似物。

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-07-24 DOI: 10.1021/acs.jmedchem.5c01192

Adam Ard,Carlos Cruz-Cortés,Xinmin Gan,Guadalupe Guerrero-Serna,Andrew D White,Martin C Clasby,L Michel Espinoza-Fonseca

{"title":"SAR-Guided Development of Small-Molecule SERCA2a Activators: Discovery of Potent Indoline, Benzofuran, and Benzodioxole Analogs for Cardiovascular Applications.","authors":"Adam Ard,Carlos Cruz-Cortés,Xinmin Gan,Guadalupe Guerrero-Serna,Andrew D White,Martin C Clasby,L Michel Espinoza-Fonseca","doi":"10.1021/acs.jmedchem.5c01192","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01192","url":null,"abstract":"Heart failure (HF) remains a major public health burden, with current therapies focused primarily on symptom management. Impaired activity of the cardiac Ca2+ pump SERCA2a is a hallmark of HF and a promising therapeutic target, but limited structural data have hindered small-molecule development. Here, we report a comprehensive structure-activity relationship (SAR) investigation of small-molecule SERCA2a activators, beginning with natural product hits and progressing through iterative optimization of three pharmacophoric regions. This effort produced the largest collection of SERCA2a modulators to date─including 20 activators, 8 dual effectors, and 6 inhibitors. Several indoline, benzofuran, and benzodioxole analogs emerged as potent activators, increasing ATPase activity by ∼57% (EC50 = 0.7-9 μM). Notably, SERCA2a activation was inversely correlated with Ca2+ affinity, suggesting that SERCA2a stimulation occurs at the expense of Ca2+ binding. In summary, these findings identify key structural features that drive SERCA2a activity and establish a framework for developing next-generation SERCA2a-targeted therapies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693350","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