Journal of Medicinal Chemistry最新文献_第9页

Development of Next-Generation ALDH1B1 Inhibitors with Enhanced Pharmacological and Functional Properties 具有增强药理和功能特性的下一代ALDH1B1抑制剂的开发

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-09 DOI: 10.1021/acs.jmedchem.5c03612

A. Kaan Tarhan,Zhiping Feng,Daniel Fernandez,Audrey Y. Kim,Thomas E. Bearrood,Andrew Hinman,Stefania Demuro,Adrianne M. Kinsey,Nicholas R. White,James K. Chen

{"title":"Development of Next-Generation ALDH1B1 Inhibitors with Enhanced Pharmacological and Functional Properties","authors":"A. Kaan Tarhan,Zhiping Feng,Daniel Fernandez,Audrey Y. Kim,Thomas E. Bearrood,Andrew Hinman,Stefania Demuro,Adrianne M. Kinsey,Nicholas R. White,James K. Chen","doi":"10.1021/acs.jmedchem.5c03612","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03612","url":null,"abstract":"Abstract ALDH1B1 is a mitochondrial aldehyde dehydrogenase required for the survival of stem-like colorectal and pancreatic cancer cells. Isoform-selective guanidinyl antagonists of aldehyde dehydrogenases (IGUANAs) have been developed for ALDH1B1, and here we describe structure−activity relationship (SAR) studies of three scaffold components: the bicyclic guanidine core, a substituted aryl ring that engages the catalytic site, and a biaryl group that interacts with flanking residues. We further show that previously reported IGUANAs are metabolically labile and rapidly effluxed from intestinal epithelial cells. To address these limitations, we have explored bioisosteres of the biaryl moiety and modifications of the guanidine core. These investigations have yielded the aryl-alkyl ether derivative IGUANA-5, a potent ALDH1B1 inhibitor that selectively blocks the growth of colon and pancreatic cancer spheroids and exhibits enhanced in vitro and in vivo pharmacological properties. Our findings establish a new class of ALDH1B1 inhibitors that could inform the advancement of anti-cancer therapies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"33 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151475","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 Diaryl Pyrimidine-Guanidine Derivatives as Jumonji C Domain-Containing Lysine Histone Demethylase (KDM) Inhibitors with In Vivo Anti-Cervical Cancer Activity 二芳基嘧啶-胍类衍生物作为含聚蒙基C结构域赖氨酸组蛋白去甲基酶（KDM）抑制剂的体内抗宫颈癌活性的发现

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-09 DOI: 10.1021/acs.jmedchem.6c01994

Dongxuan Ni,Ting Wang,Jijian Yang,Liwei Wang,Yuhan Shao,Fang Huang,Sihui Xu,Pan Liu,Xinzhu Liu,Yuanlan Ji,Ruihan Zhang,Chao Rong,Weilie Xiao

{"title":"Discovery of Diaryl Pyrimidine-Guanidine Derivatives as Jumonji C Domain-Containing Lysine Histone Demethylase (KDM) Inhibitors with In Vivo Anti-Cervical Cancer Activity","authors":"Dongxuan Ni,Ting Wang,Jijian Yang,Liwei Wang,Yuhan Shao,Fang Huang,Sihui Xu,Pan Liu,Xinzhu Liu,Yuanlan Ji,Ruihan Zhang,Chao Rong,Weilie Xiao","doi":"10.1021/acs.jmedchem.6c01994","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01994","url":null,"abstract":"Abstract JMJD family histone demethylases are highly expressed in cervical cancer and promote tumor progression, highlighting their potential as therapeutic targets for this malignancy. Using a scaffold-hopping-based virtual screening, we discovered a series of diaryl pyrimidine-guanidine derivatives as KDM6B inhibitors. The optimized compound 40 exhibited potent KDM6B inhibitory activity comparable to that of GSK-J4, but differs mechanistically by being non-competitive with 2-OG. Although 40 showed pan-KDM inhibition in enzymatic level, it selectively elevated H3K27me3 levels in C33A cells without affecting H3K4me3 or H3K9me3. In C33A cells, 40 suppressed proliferation, induced cell-cycle arrest and apoptosis. In a xenograft mouse model, 40 inhibited tumor growth, downregulated Ki-67, and upregulated cleaved caspase-3, p-H2A.X, and H3K27me3. Collectively, 40 represents a promising chemical probe for investigating JMJD KDMs and H3K27 modifications in cervical cancer and establishes a foundation for developing targeted agents.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151434","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

Beyond Inhibition: Targeted Degradation of NLRP3 by Autophagy-Tethering Bifunctional Compounds as a Therapy for Inflammatory Bowel Disease 超越抑制：自噬-栓系双功能化合物靶向降解NLRP3作为炎症性肠病的治疗方法

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-09 DOI: 10.1021/acs.jmedchem.6c01995

Xinru Zheng,Yongxing Xue,Hongyu Wu,Chenjia Liu,Yingxin Wang,Kehuan Wu,Xiaohao Xie,Shaozong Ma,Xianfeng Gu,Ziwen Zhang,Ying Chen

引用次数: 0

Development of Potent G Protein Pathway-Biased GPR183 Agonists 强效G蛋白通路偏倚GPR183激动剂的研制

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-09 DOI: 10.1021/acs.jmedchem.6c01079

Kaustubh R. Bhuskute,Asmita Manandhar,Viktoria M. S. Kjær,Francesco Casartelli,Gertrud M. Hjortø,Maria Ioanna Koutsaki,Udhayabhaskar Sathyanarayanan,Emilia Hjortkilde,Rita Turcio,Mette M. Rosenkilde,Trond Ulven,Elisabeth Rexen Ulven

{"title":"Development of Potent G Protein Pathway-Biased GPR183 Agonists","authors":"Kaustubh R. Bhuskute,Asmita Manandhar,Viktoria M. S. Kjær,Francesco Casartelli,Gertrud M. Hjortø,Maria Ioanna Koutsaki,Udhayabhaskar Sathyanarayanan,Emilia Hjortkilde,Rita Turcio,Mette M. Rosenkilde,Trond Ulven,Elisabeth Rexen Ulven","doi":"10.1021/acs.jmedchem.6c01079","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01079","url":null,"abstract":"Abstract GPR183 is an oxysterol-sensing GPCR predominantly expressed in lymphoid organs and tissues. Activation of the receptor by oxysterol 7α,25-OHC leads to Gαi protein-mediated signaling as well as β-arrestin2 recruitment. GPR183/oxysterol signaling modulates localization of lymphoid cells; consequently, the receptor is associated with several inflammation-associated diseases and is an interesting potential drug target. Previously, we reported the discovery of moderately potent G protein-biased partial agonists for GPR183 from a virtual screening based on the antagonist NIBR189. Herein, we present the detailed structure−activity investigations and optimizations, which led to the identification of full agonists for GPR183 with complete bias for G protein signaling and low nanomolar potency, including 63 (TUG-2604) with potency and efficacy similar to 7α,25-OHC. Notably, 63 was unable to induce migration of human dendritic cells but inhibited migration induced by 7α,25-OHC. This compound will be valuable for further explorations of the signaling-specific function and drug target potential of GPR183.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"29 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151437","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

Simplification and Derivatization of Quinoline-Containing M41 Lead to the Discovery of NADPH Oxidase Isoform-Selective Inhibitors Effective in Cancer Cells 含有喹啉的M41的简化和衍生化导致发现对癌细胞有效的NADPH氧化酶异构体选择性抑制剂

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-09 DOI: 10.1021/acs.jmedchem.6c02029

Chiara Lambona,Sara Marchese,Beatrice Noce,Marta Massari,Davide Ciampoli,Francesco Fiorentino,Clemens Zwergel,Emanuele Fabbrizi,Andrea Mancini,Francesco Quilli,Federico Pandolfi,Alessia Raucci,Rossella Fioravanti,Davide Corinti,Matteo Re,Alessandro Mormino,Stefano Garofalo,Cristina Limatola,Donato Mele,Lucia Capasso,Rosaria Casalino,Angela Nebbioso,Lucia Altucci,Domenico Raimondo,Andrea Mattevi,Antonello Mai,Sergio Valente

{"title":"Simplification and Derivatization of Quinoline-Containing M41 Lead to the Discovery of NADPH Oxidase Isoform-Selective Inhibitors Effective in Cancer Cells","authors":"Chiara Lambona,Sara Marchese,Beatrice Noce,Marta Massari,Davide Ciampoli,Francesco Fiorentino,Clemens Zwergel,Emanuele Fabbrizi,Andrea Mancini,Francesco Quilli,Federico Pandolfi,Alessia Raucci,Rossella Fioravanti,Davide Corinti,Matteo Re,Alessandro Mormino,Stefano Garofalo,Cristina Limatola,Donato Mele,Lucia Capasso,Rosaria Casalino,Angela Nebbioso,Lucia Altucci,Domenico Raimondo,Andrea Mattevi,Antonello Mai,Sergio Valente","doi":"10.1021/acs.jmedchem.6c02029","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02029","url":null,"abstract":"Abstract NADPH oxidases (NOXs) are attractive but challenging drug targets. Starting from M41 and its analog MC4876, we synthesized quinoline-based derivatives. SAR studies revealed that modifications at the quinoline C2 position and the amine-moiety influenced potency and isoform preference. Boc-protected analogs preferred NOX5, (compound 1a: IC50 = 1.6 μM), whereas deprotected derivatives favored NOX2. Replacing piperidine with tetrahydropyran afforded 1e, a selective NOX1 inhibitor (IC50 = 3.4 μM). The bisquinoline derivative 2a emerged as the most potent, selective NOX2 inhibitor (IC50 = 1.4 μM; cellular EC50 = 0.89 μM). Computational studies support binding at the NADPH site and attribute 2a′s enhanced potency to additional interactions. MC4876 displayed antiproliferative activity, reducing glioblastoma cell viability, glucose uptake, HK2 expression, and mesenchymal markers, while lowering ROS and inducing mitochondrial dysfunction and DNA damage in U937 cells. These findings identify quinoline as tunable scaffolds for isoform-selective NOX inhibition, with 1e and 2a as promising leads.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"190 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151476","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 Potent and Selective VHL-Recruiting PROTAC Degraders Targeting EGFR with Improved Developability and Potent Anti-NSCLC Efficacy 靶向EGFR的高效和选择性vhl招募PROTAC降降剂的发现，具有更好的可发展性和有效的抗nsclc疗效

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-08 Epub Date: 2026-09-18 DOI: 10.1021/acs.jmedchem.6c01893

Xiang Ni, Mei Li, Jinglin Tang, Zhihao Qi, Ying Zhou, Zepeng Liao, Yiyun Song, Qi Miao, Zhiyi Zhang, Sheng Jiang, Yibei Xiao, Kuojun Zhang

{"title":"Discovery of Potent and Selective VHL-Recruiting PROTAC Degraders Targeting EGFR with Improved Developability and Potent Anti-NSCLC Efficacy","authors":"Xiang Ni, Mei Li, Jinglin Tang, Zhihao Qi, Ying Zhou, Zepeng Liao, Yiyun Song, Qi Miao, Zhiyi Zhang, Sheng Jiang, Yibei Xiao, Kuojun Zhang","doi":"10.1021/acs.jmedchem.6c01893","DOIUrl":"10.1021/acs.jmedchem.6c01893","url":null,"abstract":"Epidermal growth factor receptor (EGFR) kinase inhibitors have revolutionized non-small cell lung cancer (NSCLC) treatment; however, the inevitable acquired resistance necessitates alternative strategies beyond conventional inhibition. Herein, we report the discovery and optimization of VHL-recruiting PROTAC degraders targeting the EGFR. Representative compounds C4 and D4 demonstrated potent, selective, and durable degradation of EGFRDel19 (C4: DC50 = 1.41 nM, Dmax = 99%; D4: DC50 = 9.14 nM, Dmax = 98%) and EGFRL858R (C4: DC50 = 3.30 nM, Dmax = 95%; D4: DC50 = 15.2 nM, Dmax = 98%). C4 induced cell cycle arrest and apoptosis, displayed subnanomolar antiproliferative activity, and drove significant tumor regression in an HCC827 xenograft model at low intravenous doses with a reduced twice-weekly schedule. Remarkably, D4 was orally bioavailable (F = 11.3%) and blood−brain barrier penetrant and completely inhibited tumor growth in vivo after oral dosing. Overall, this work provides promising starting points for next-generation EGFR-directed therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"22671–22698"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003506","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

A Selective ERα Photodegrader for Precise and Efficient Breast Cancer Treatment 选择性ERα光降解剂用于精确有效的乳腺癌治疗

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-08 Epub Date: 2026-09-25 DOI: 10.1021/acs.jmedchem.6c00904

Ziwei Wang, Xin Ding, Zhao Li, Yu Zhang, Qizhang Li, Kangkang Li, Jian Min, Juan Xu, Weidong Pan, Huan He, Chang Min, Silong Zhang

{"title":"A Selective ERα Photodegrader for Precise and Efficient Breast Cancer Treatment","authors":"Ziwei Wang, Xin Ding, Zhao Li, Yu Zhang, Qizhang Li, Kangkang Li, Jian Min, Juan Xu, Weidong Pan, Huan He, Chang Min, Silong Zhang","doi":"10.1021/acs.jmedchem.6c00904","DOIUrl":"10.1021/acs.jmedchem.6c00904","url":null,"abstract":"Breast cancer is the most prevalent malignancy in women, with over 70% of cases being estrogen receptor α (ERα)-positive. Photodynamic therapy (PDT) is spatially precise yet limited by tumor-selective photosensitizers. Herein, we report the first co-crystal structure of 2,2′-dihydroxytriphenylamine bound to ERα, which provided a structural blueprint for designing EP5, an innovative ERα-targeted photodegrader. EP5 exhibits high binding affinity toward ERα (KD = 56.7 nM), enabling its selective accumulation in ERα-positive breast cancer cells. Upon white-light irradiation, EP5 triggers selective ERα degradation without affecting ERβ. It potently suppresses ERα-positive cancer cell proliferation (IC50 = 0.54 μM, selectivity index >185). Systemic EP5 administration plus light achieves complete xenograft tumor regression (TGI = 105.3%) with no detectable systemic toxicity. EP5 is a promising candidate for precision breast cancer therapy. By simultaneously achieving tumor selectivity, therapeutic efficacy, and safety, EP5 represents a promising precision oncology platform for clinical translation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"21902–21918"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049671","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

Lysosome-Targeted Iridium(III) Photosensitizers Activate the Mitophagy−Ferroptosis Axis to Boost Two-Photon Photoimmunotherapy Against Hypoxic Cisplatin-Resistant Tumors 溶酶体靶向铱（III）光敏剂激活Mitophagy - Ferroptosis轴，促进双光子光免疫治疗低氧顺铂耐药肿瘤

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-08 Epub Date: 2026-09-23 DOI: 10.1021/acs.jmedchem.6c02622

Hui Jiang, Qiaoshan Lie, Fa Wang, Shufei Li, Jinrong Yang, Wanhe Wang, Taihong Liu, Johannes Karges, Hui Chao

{"title":"Lysosome-Targeted Iridium(III) Photosensitizers Activate the Mitophagy−Ferroptosis Axis to Boost Two-Photon Photoimmunotherapy Against Hypoxic Cisplatin-Resistant Tumors","authors":"Hui Jiang, Qiaoshan Lie, Fa Wang, Shufei Li, Jinrong Yang, Wanhe Wang, Taihong Liu, Johannes Karges, Hui Chao","doi":"10.1021/acs.jmedchem.6c02622","DOIUrl":"10.1021/acs.jmedchem.6c02622","url":null,"abstract":"Hypoxia and immunosuppression limit photodynamic therapy (PDT) in treatment-resistant solid tumors. We developed structure-guided, lysosome-targeted Ir(III) photosensitizers and identified a symmetric, π-conjugation-extended dinuclear complex with 810 nm two-photon activation, high singlet-oxygen quantum yield, low dark cytotoxicity, and sustained type-I reactive oxygen species generation under hypoxia. Photoactivation triggered lysosomal membrane permeabilization, cathepsin B release, Ca(II) dysregulation, mitochondrial depolarization, and PINK1-associated mitophagy. This lysosome-to-mitochondria stress relay depleted GSH, inactivated GPX4, increased Fe(II) and lipid peroxidation, and sensitized cisplatin-resistant lung cancer cells to ferroptosis. In a sequential contralateral CMT167 rechallenge model, local treatment suppressed primary tumor growth and delayed the growth of a subsequently implanted, non-irradiated contralateral tumor, accompanied by broad remodeling of the tumor immune microenvironment. These findings establish a hypoxia-tolerant dinuclear photosensitizer that couples two-photon PDT to ferroptosis and systemic antitumor immune activation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"23042–23054"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149021856","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

Structure-Based Optimization of 2-Aminopyrimidine Derivatives as Potent Multi-target FLT3/CHK1/IRAK4 Inhibitors for Acute Myeloid Leukemia 基于结构优化的2-氨基嘧啶衍生物多靶点FLT3/CHK1/IRAK4抑制剂治疗急性髓系白血病

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-08 Epub Date: 2026-09-23 DOI: 10.1021/acs.jmedchem.6c01936

Xuemei Li, Kailong Jiang, Luyao Zhang, Xinyan Lan, Xiaozhen Chen, Ran Xu, Yue Gao, Peipei Wang, Xiaobei Hu, Yubo Zhou, Jia Li, Tao Liu

{"title":"Structure-Based Optimization of 2-Aminopyrimidine Derivatives as Potent Multi-target FLT3/CHK1/IRAK4 Inhibitors for Acute Myeloid Leukemia","authors":"Xuemei Li, Kailong Jiang, Luyao Zhang, Xinyan Lan, Xiaozhen Chen, Ran Xu, Yue Gao, Peipei Wang, Xiaobei Hu, Yubo Zhou, Jia Li, Tao Liu","doi":"10.1021/acs.jmedchem.6c01936","DOIUrl":"10.1021/acs.jmedchem.6c01936","url":null,"abstract":"The efficacy of FLT3 inhibitors is limited by resistance. Co-inhibiting FLT3 and CHK1 can overcome FLT3i resistance, and IRAK4 signaling contributes to leukemic cell survival in FLT3-mutant acute myeloid leukemia (AML). We discovered a novel series of 2-aminopyrimidine derivatives as potent multi-target FLT3/CHK1/IRAK4 inhibitors. Among them, compound 33 exhibited potent activity against FLT3-WT (IC50 = 5.05 nM), FLT3-D835Y (IC50 = 2.99 nM), CHK1 (IC50 = 33.32 nM), and IRAK4 (IC50 = 15.94 nM), with 85-fold selectivity over c-KIT. Moreover, it potently inhibited FLT3-mutant BaF3 cells and blocked FLT3/CHK1/IRAK4 signaling, upregulating p53/p21 and downregulating PD-L1. It overcame cytokine-induced resistance in MV-4-11 cells. In vivo, 33 significantly suppressed tumor growth in MV-4-11 xenografts (TGI = 84.96% at 5 mg/kg) and prolonged survival (from 40.5 days to 61.5 days) in a disseminated AML model without toxicity. These results demonstrate that 33 is a promising multi-target inhibitor candidate for FLT3-mutant AML.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"22737–22765"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149021861","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

Two-Step Design of Triazole-Stapled Opioid Agonists Exhibiting Potent and Prolonged Peripheral Analgesic Activity 三唑类阿片受体激动剂的两步设计，显示出有效和持久的外周镇痛活性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-08 Epub Date: 2026-09-22 DOI: 10.1021/acs.jmedchem.6c01096

Mengna Zhang, Jie Gao, Jiamin Feng, Zefei Wang, Xia Wang, Zixiao Wang, Bowen Yu, Yongpeng Liu, Sha Hu, Biao Xu, Ning Li, Feiyun Gao, Quan Fang

{"title":"Two-Step Design of Triazole-Stapled Opioid Agonists Exhibiting Potent and Prolonged Peripheral Analgesic Activity","authors":"Mengna Zhang, Jie Gao, Jiamin Feng, Zefei Wang, Xia Wang, Zixiao Wang, Bowen Yu, Yongpeng Liu, Sha Hu, Biao Xu, Ning Li, Feiyun Gao, Quan Fang","doi":"10.1021/acs.jmedchem.6c01096","DOIUrl":"10.1021/acs.jmedchem.6c01096","url":null,"abstract":"This study establishes a two-step strategy for developing triazole-stapled multifunctional agonists that integrate opioid and neuropeptide FF (NPFF) pharmacophores. Initially, calcium mobilization assays, enzymatic stability tests, and analgesic activity screens identified triazole-stapled opioid peptide 16, derived from the opioid pharmacophore of the multifunctional opioid/NPFF agonist DN-9. Subsequently, chimeric conjugation of 16 with the NPFF pharmacophore yielded the novel multitarget analgesic agonist, 16a. Functional assays demonstrated that 16 functions as a μ-opioid receptor (MOR) agonist and a δ-opioid receptor partial agonist, while 16a exhibits multitarget activity at MOR, κ-opioid receptor, and NPFF receptors, with G-protein-biased signaling at MOR. Pharmacological evaluations revealed that subcutaneous administration of both compounds elicited sustained dose-dependent antinociceptive effects across acute and visceral pain models. Notably, these compounds exhibited diminished propensity for addiction and respiratory depression and furthermore produced nontolerant antinociception via an NPFF receptor-independent pathway. This strategy offers a promising framework for developing long-lasting analgesics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"21987–22007"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149021870","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