Journal of Medicinal Chemistry最新文献_第2页

Discovery and Optimization of Indole-Based CDK9 Inhibitors for Hepatocellular Carcinoma 吲哚基CDK9肝细胞癌抑制剂的发现与优化

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-20 DOI: 10.1021/acs.jmedchem.6c01374

Tizhi Wu,Wenyi Zhou,Feihai Ma,Zexu Wang,Jingyi Ding,Jing Liu,Yifang Liu,Shiqi Wu,Zhixia Qiu,Kaibo Wang,Zhiyu Li,Hongxi Wu,Jinlei Bian

{"title":"Discovery and Optimization of Indole-Based CDK9 Inhibitors for Hepatocellular Carcinoma","authors":"Tizhi Wu,Wenyi Zhou,Feihai Ma,Zexu Wang,Jingyi Ding,Jing Liu,Yifang Liu,Shiqi Wu,Zhixia Qiu,Kaibo Wang,Zhiyu Li,Hongxi Wu,Jinlei Bian","doi":"10.1021/acs.jmedchem.6c01374","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01374","url":null,"abstract":"CDK9 has emerged as a promising therapeutic target for anticancer drug development. Although multiple CDK9 inhibitors have entered clinical evaluation, differentiated scaffolds with convincing activity and tolerability in solid tumors remain limited. In this study, we identified a series of indole-based CDK9 inhibitors through virtual screening and structure-based drug design, and systematically evaluated their therapeutic potential in hepatocellular carcinoma (HCC). Among these compounds, W24 exhibited potent CDK9 inhibitory activity (IC50 = 0.9 nM) and a preliminary kinase selectivity profile. W24 effectively induced HCC cell death in vitro, which was accompanied by DNA damage and downregulation of the anti-apoptotic protein Mcl-1. Furthermore, W24 significantly suppressed tumor growth in HepG2 and Huh-7 xenograft models with an acceptable safety profile under the tested dosing regimen. Collectively, these findings highlight W24 as a promising lead compound and provide valuable insights for the development of next-generation CDK9 inhibitors for the treatment of hepatocellular carcinoma.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"225 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221695","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

Influence of Fluorine Substitution Pattern in Arylboronic Acid Caps on the Myocardial Perfusion Imaging Properties of Technetium Monocapped Tris(dioxime) Complexes 芳基硼酸帽中氟取代模式对锝单包三（二肟）配合物心肌灌注成像特性的影响

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-20 DOI: 10.1021/acs.jmedchem.6c02123

Ding Ding,Wanjie Ren,Yufan Gu,Min Ju,Yue Zhou,Shuyang Song,Ke Wang,Zongyao Zhang,Lei Wang,Wei Fang

{"title":"Influence of Fluorine Substitution Pattern in Arylboronic Acid Caps on the Myocardial Perfusion Imaging Properties of Technetium Monocapped Tris(dioxime) Complexes","authors":"Ding Ding,Wanjie Ren,Yufan Gu,Min Ju,Yue Zhou,Shuyang Song,Ke Wang,Zongyao Zhang,Lei Wang,Wei Fang","doi":"10.1021/acs.jmedchem.6c02123","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02123","url":null,"abstract":"Boronate-based myocardial perfusion tracers represent a promising scaffold for quantitative SPECT myocardial blood flow (MBF) imaging. In this study, five fluorinated 99mTc-labeled boronate derivatives were designed to systematically investigate the influence of fluorine substitution patterns on tracer pharmacokinetics and imaging performance. The fluorination pattern markedly influenced myocardial uptake, hepatic clearance, and overall biodistribution, with 99mTc-2F-HMPBA (99mTc-2F) and 99mTc-3F-HMPBA (99mTc-3F) exhibiting the most favorable profiles. Mechanistic evaluation using isolated heart perfusion demonstrated a high first-pass extraction fraction over a wide range of coronary flow rates, while dynamic SPECT imaging in swine showed tracer-derived K1 values comparable to 13N−NH3 PET-derived MBF. In particular, 99mTc-3F exhibited a more balanced pharmacokinetic profile with improved heart-to-liver contrast. These findings establish fluorine substitution as an effective strategy for tuning the pharmacokinetic behavior of boronate-based myocardial perfusion tracers and identify 99mTc-3F as a promising lead for quantitative SPECT myocardial perfusion imaging.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"56 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221748","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

Design, Synthesis, and Biological Evaluation of Novel Benzimidazole Derivatives as Dual PI3K/HDAC8 Inhibitors with Potent Anti-Cervical Cancer Activity InVivo 新型苯并咪唑衍生物作为PI3K/HDAC8双抑制剂的设计、合成和生物学评价

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-20 DOI: 10.1021/acs.jmedchem.6c01456

Junjie Chen,Weixu Wang,Xijin Qi,Naziyila Shayilan,Weiyi Zhang,Cheng Ma

引用次数: 0

Discovery of Pyrazolo[1,5-a]-1,3,5-Triazine Derivatives as Potent, Highly Selective and Orally Available Macrocyclic CDK7 Inhibitors 吡唑啉[1,5-a]-1,3,5-三嗪衍生物作为有效、高选择性和口服大环CDK7抑制剂的发现

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-20 DOI: 10.1021/acs.jmedchem.6c01660

Quanpeng Wei,Yanxin Tao,Xinpeng Ning,Suyun Jia,Yan Chen,Xiaoli Du,Xinyu Sun,Lingrui Xu,Xinrui Jiang,Pengpeng Niu,Mengyang Fan,Yupeng Li,Dawei Ma,Shan Li,Ke Ding

{"title":"Discovery of Pyrazolo[1,5-a]-1,3,5-Triazine Derivatives as Potent, Highly Selective and Orally Available Macrocyclic CDK7 Inhibitors","authors":"Quanpeng Wei,Yanxin Tao,Xinpeng Ning,Suyun Jia,Yan Chen,Xiaoli Du,Xinyu Sun,Lingrui Xu,Xinrui Jiang,Pengpeng Niu,Mengyang Fan,Yupeng Li,Dawei Ma,Shan Li,Ke Ding","doi":"10.1021/acs.jmedchem.6c01660","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01660","url":null,"abstract":"Cyclin-dependent kinase 7 (CDK7) is a promising cancer therapeutic target due to its dual role in cell cycle progression and gene transcription. However, current CDK7 inhibitors generally exhibit poor kinase selectivity. Herein, we performed in-depth structural optimization on a 17-membered macrocyclic scaffold, and identified compound I-23, which potently inhibits CDK7 with an IC50 value of 3 nM and exhibits exceptional CDK7 selectivity with no significant off-target activity across 416 kinases. I-23 also potently inhibits cell proliferation across a panel of tumor cell lines, induces cell cycle arrest and transcriptional suppression, and downregulates oncoprotein c-Myc, particularly in triple-negative breast cancer cells. Importantly, I-23 shows favorable oral bioavailability (up to 28%) with linear pharmacokinetics. Collectively, this work provides a highly selective and orally bioavailable macrocyclic CDK7 inhibitor, which can serve as a valuable chemical tool for dissecting CDK7 biological functions and a promising lead compound for CDK7-based anticancer drug discovery.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221698","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

From Ubiquitination to Proteasome-Directed Recruiting: Emerging Mechanisms and Therapeutic Potential in Targeted Protein Degradation 从泛素化到蛋白酶体定向招募：靶向蛋白质降解的新机制和治疗潜力

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-20 DOI: 10.1021/acs.jmedchem.6c01098

Yaoli Shi,Jiayi Ma,Yutong Tu,Qingyi Wang,Mingzhi Wang,Jiaan Shao,Guifeng Wang,Jia Li,Huajian Zhu,Yubo Zhou,Jiankang Zhang

{"title":"From Ubiquitination to Proteasome-Directed Recruiting: Emerging Mechanisms and Therapeutic Potential in Targeted Protein Degradation","authors":"Yaoli Shi,Jiayi Ma,Yutong Tu,Qingyi Wang,Mingzhi Wang,Jiaan Shao,Guifeng Wang,Jia Li,Huajian Zhu,Yubo Zhou,Jiankang Zhang","doi":"10.1021/acs.jmedchem.6c01098","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01098","url":null,"abstract":"Targeted protein degradation has transformed drug discovery by enabling selective elimination of disease-associated proteins. Beyond classical E3 ligase-recruiting degraders, emerging proteasome-directed strategies seek to recruit targets directly to the proteasome, potentially bypassing E3 ligase dependency and ubiquitination requirements. This approach may expand the degradable proteome, but requires proteasome ligands that engage accessible surfaces, tolerate linker attachment, and preserve basal proteasome function. In this Perspective, we summarize recent advances in direct proteasome-targeting degradation, focusing on ligands of the 19S regulatory particle and 20S core particle. We assess how proteasome subunits and binding pockets have been exploited for degrader design and distinguish ligand-level challenges, such as undefined binding sites, immature SAR, and uncertain linker vectors, from degrader-level issues, including cellular exposure, degradation selectivity, off-target effects, and proteostasis liability. These considerations provide a framework for designing next-generation proteasome-recruiting degraders.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221741","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 Neurolysin Activators with Preclinical Efficacy in an Ischemic Stroke Model 在缺血性脑卒中模型中具有临床前疗效的神经溶解素激活剂的发现

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-20 DOI: 10.1021/acs.jmedchem.6c02108

Shikha Kumari,Krishnaiah Maddeboina,Shiva Hadi Esfahani,Shirisha Jonnalagadda,Xiaoyu Hao,Aarfa Queen,Yong Zhang,Asmaa Aly,Haya Kandil,Saeideh Nozohouri,Hossam Elaraky,Thomas J. Abbruscato,Vardan T. Karamyan,Paul C. Trippier

{"title":"Discovery of Neurolysin Activators with Preclinical Efficacy in an Ischemic Stroke Model","authors":"Shikha Kumari,Krishnaiah Maddeboina,Shiva Hadi Esfahani,Shirisha Jonnalagadda,Xiaoyu Hao,Aarfa Queen,Yong Zhang,Asmaa Aly,Haya Kandil,Saeideh Nozohouri,Hossam Elaraky,Thomas J. Abbruscato,Vardan T. Karamyan,Paul C. Trippier","doi":"10.1021/acs.jmedchem.6c02108","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02108","url":null,"abstract":"The peptidase neurolysin (Nln) is upregulated following ischemic stroke to activate endogenous cerebroprotective mechanisms and has subsequently emerged as a therapeutic target for drug discovery efforts. Overexpression of Nln in a mouse model of ischemic stroke results in significant improvement of stroke outcomes. Herein, we report the discovery of the first non-peptide Nln activators based around a central pyridine-piperazine scaffold that possesses nanomolar potency. This scaffold, exemplified by compounds 7c and 7g, exhibits greater in vitro half-life, blood−brain barrier penetration, mouse brain and mouse plasma stability than previously reported peptidomimetic Nln activators. Compound 7g afforded an in vivo protective effect in the MCAO mouse model of ischemic stroke, significantly reducing infarct volume and brain water content, marking the first report of a small molecule Nln activator with in vivo cerebroprotective effects in a preclinical model.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221746","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

Design and Biological Evaluation of FAP-Man, a Mannosylated FAP-Targeted Radioglycopeptide for Tumor Imaging and Radionuclide Therapy 一种用于肿瘤成像和放射性核素治疗的甘露糖基化FAP-Man的设计和生物学评价

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-20 DOI: 10.1021/acs.jmedchem.6c02436

Miaomiao Song,Entao Liu,Rui Cao,Luming Sun,Peng Wang,Shuang Duan,Ji Tao,Long Qiu,Jin Du,Ning Liu,Feize Li,Chunrong Qu,Lei Jiang,Zhen Cheng

引用次数: 0

Development and Preclinical Evaluation of Six-Transmembrane Epithelial Antigen of Prostate 2 Targeted PET Probes: A Case of Drug Repurposing Based on Molecular Docking 前列腺2靶向PET探针六跨膜上皮抗原的研制及临床前评价：基于分子对接的药物再利用案例

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-20 DOI: 10.1021/acs.jmedchem.6c01270

Zhuoyi Deng,Wenyuan Zhou,Chen Liu,Chao Liu,Honglei Zhang,Yifei Pei,Lulin Yang,Hua Zhu,Zhi Yang,Teli Liu

{"title":"Development and Preclinical Evaluation of Six-Transmembrane Epithelial Antigen of Prostate 2 Targeted PET Probes: A Case of Drug Repurposing Based on Molecular Docking","authors":"Zhuoyi Deng,Wenyuan Zhou,Chen Liu,Chao Liu,Honglei Zhang,Yifei Pei,Lulin Yang,Hua Zhu,Zhi Yang,Teli Liu","doi":"10.1021/acs.jmedchem.6c01270","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01270","url":null,"abstract":"Six-transmembrane epithelial antigen of prostate 2 (STEAP2) is overexpressed in prostate cancer, yet no STEAP2-targeted imaging probes exist. Using molecular docking, we screened triptorelin and leuprorelin by radioiodine labeling and identified triptorelin as a high-affinity, selective ligand. To enhance in vivo stability and pharmacokinetics, triptorelin underwent acetylation, PEG extension, and 4-iodophenylbutyric acid conjugation, yielding five DOTA-conjugated analogs radiolabeled with 68Ga. In 22Rv1 xenografts, 68Ga-Trip-5 exhibited moderate but specific tumor uptake (SUVmax 1.8) with favorable tumor-to-background contrast. In vivo stability, biodistribution, pharmacokinetics, and human radiation dosimetry (effective dose 0.00345 mSv/MBq) demonstrated favorable safety. Autoradiography on human prostate cancer specimens showed probe accumulation correlating with endogenous STEAP2 expression. This represents the first STEAP2-targeted PET probe developed via molecular docking-guided drug repurposing. Cellular, biochemical, and imaging data provide supportive evidence of STEAP2-mediated targeting. Preclinical performance supports clinical translation of 68Ga-Trip-5, with definitive target validation","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"45 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221762","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

Synthesis and In Vitro/In Vivo Stability Evaluation of Various Radioiodinated Tyrosine Derivatives 多种放射性碘化酪氨酸衍生物的合成及体外/体内稳定性评价

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-20 DOI: 10.1021/acs.jmedchem.6c02347

Weiqi Liu,Minhao Liang,Taiwei Chu

引用次数: 0

Design and Synthesis of Novel, Non-ATP-Competitive MKK3 Modulators as Suppressors of TNF-α Production for the Treatment of Ulcerative Colitis 设计和合成新型非atp竞争性MKK3调节剂，抑制TNF-α的产生，治疗溃疡性结肠炎

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-20 DOI: 10.1021/acs.jmedchem.6c01880

Buyu Kou,Mengxiao Zhuang,Tong Song,Xin Liu,Chao Peng,Haixia Liu,Mingliang Wang,Xun Sun

{"title":"Design and Synthesis of Novel, Non-ATP-Competitive MKK3 Modulators as Suppressors of TNF-α Production for the Treatment of Ulcerative Colitis","authors":"Buyu Kou,Mengxiao Zhuang,Tong Song,Xin Liu,Chao Peng,Haixia Liu,Mingliang Wang,Xun Sun","doi":"10.1021/acs.jmedchem.6c01880","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01880","url":null,"abstract":"Although TNF-α is a clinically validated target for Ulcerative colitis (UC), therapy is dominated by injectable biologics, with no oral small-molecule inhibitors approved. Traditional ATP-competitive p38 inhibitors designed to regulate TNF-α have failed in clinical trials due to poor kinome selectivity. As the primary upstream activator of p38, MKK3 is considered a promising alternative target, but the development of small molecules remains limited, with a notable absence of non-ATP-competitive modulators. Herein, we report a series of compounds targeting the non-ATP-competitive pocket of MKK3 to suppress TNF-α production. Among them, (R)-48 was identified as a lead candidate, demonstrating robust suppression of TNF-α (IC50: 0.038 μM), high oral bioavailability (62.6%), clear dose-dependent efficacy and strong PK/PD relationships in mouse UC models. Particularly, HDX-MS suggested (R)-48 probably binds to a distal allosteric site on MKK3, precluding TAK1-mediated activation. Altogether, (R)-48 emerges as a promising oral small-molecule therapeutic candidate for the treatment of UC.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"34 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221761","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