Journal of Medicinal Chemistry最新文献_第3页

FGFR3 Selectivity in Drug Discovery: Biological Rationale, Design Strategies, and Therapeutic Potential 药物发现中的FGFR3选择性：生物学原理、设计策略和治疗潜力

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-19 DOI: 10.1021/acs.jmedchem.6c01963

Jacqueline H. Starrett,Daniel C. Bensen,Ronald V. Swanson,Robert L. Hudkins

{"title":"FGFR3 Selectivity in Drug Discovery: Biological Rationale, Design Strategies, and Therapeutic Potential","authors":"Jacqueline H. Starrett,Daniel C. Bensen,Ronald V. Swanson,Robert L. Hudkins","doi":"10.1021/acs.jmedchem.6c01963","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01963","url":null,"abstract":"Fibroblast growth factor receptor 3 (FGFR3) gain-of-function alterations drive a spectrum of conditions, including cancers and skeletal dysplasias, making FGFR3 an attractive therapeutic target. While second-generation pan-FGFR inhibitors established clinical proof-of-concept, their utility has been constrained by toxicities associated with inhibition of FGFR1, FGFR2, and FGFR4. Despite the high degree of structural homology within the FGFR family, structure-guided medicinal chemistry efforts have recently enabled the development of the first FGFR3-selective inhibitors to enter clinical evaluation. These agents are now being investigated for indications including bladder cancer and achondroplasia. Improved isoform selectivity has the potential to enhance tolerability, enable more durable target inhibition, and expand the therapeutic application of FGFR3-directed therapies. In this Perspective, we discuss the biological rationale for selective FGFR3 inhibition, the structure-based design strategies that have enabled FGFR3 selectivity, and emerging clinical opportunities to address unmet needs in FGFR3-driven disease.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"28 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218807","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

Evaluation of Cytotoxic Potential of Water-Soluble Photosensitive Pincer-Copper Complexes 水溶性光敏螯合铜配合物细胞毒性电位的评价

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-19 DOI: 10.1021/acs.jmedchem.6c02129

Hachina Begum,Babu Venkateshappa,Hirakjyoti Roy,Siddhartha Sankar Ghosh,Akshai Kumar

{"title":"Evaluation of Cytotoxic Potential of Water-Soluble Photosensitive Pincer-Copper Complexes","authors":"Hachina Begum,Babu Venkateshappa,Hirakjyoti Roy,Siddhartha Sankar Ghosh,Akshai Kumar","doi":"10.1021/acs.jmedchem.6c02129","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02129","url":null,"abstract":"Herein, the synthesis and characterization of four new water-soluble pincer-copper complexes of the type (R2NNN)CuCl2 (R = C6H5, p-OMe-C6H4, p-Me-C6H4, and p-F-C6H4) based on bis(imino)pyridine ligands have been reported. The complexes exhibited significant cytotoxicity against a monolayer of MCF-7 breast cancer cells following light irradiation. Notably, the complex (Ph2NNN)CuCl2 demonstrated the highest efficacy among the pincer-Cu complexes, with an IC50 of 11 μM in the presence of light and an IC50 of 25 μM in dark conditions, making it ideal for photodynamic therapy (PDT). The complex (Ph2NNN)CuCl2 demonstrated selectivity for MCF-7 cells, as indicated by its reduced cytotoxicity against HEK cells. The generation of singlet oxygen (1O2) led to photo-oxidation-mediated apoptosis, as evidenced by the Annexin V/PI assay and concomitant G2/M cell cycle arrest. Furthermore, cleaved PARP (cPARP) expression upon photoactivation also confirmed the induction of apoptosis. This work provides an avenue for future applications of strategically engineered water-soluble pincer-metal complexes in cancer phototherapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"44 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218806","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

Reducing off-Target hERG Activity of First-Generation DCN1-UBE2M Interaction Inhibitors: Design, Synthesis, and Structure−Activity Relationships 降低第一代DCN1-UBE2M相互作用抑制剂的脱靶hERG活性：设计，合成和结构-活性关系

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-19 DOI: 10.1021/acs.jmedchem.6c02207

Tara Man Kadayat,Gaurav Shoeran,Daniel C. Scott,Kristin L. Begley,Jared T. Hammill,Jong Yeon Hwang,Tucker J. Moseley,Ho Shin Kim,Agripina G. Deaciuc,Moeko T. King,Bhuvanesh Singh,Brenda A. Schulman,R. Kiplin Guy

{"title":"Reducing off-Target hERG Activity of First-Generation DCN1-UBE2M Interaction Inhibitors: Design, Synthesis, and Structure−Activity Relationships","authors":"Tara Man Kadayat,Gaurav Shoeran,Daniel C. Scott,Kristin L. Begley,Jared T. Hammill,Jong Yeon Hwang,Tucker J. Moseley,Ho Shin Kim,Agripina G. Deaciuc,Moeko T. King,Bhuvanesh Singh,Brenda A. Schulman,R. Kiplin Guy","doi":"10.1021/acs.jmedchem.6c02207","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02207","url":null,"abstract":"We previously reported a potent and orally available inhibitor (2, NAcM-OPT) of the DCN1-UBE2M protein interaction that targets the neddylation pathway to potentially regulate oncogenic transformation for the treatment of cancer. In vivo profiling of compound 2 revealed that, while it was potent, orally bioavailable, and inhibited growth of tumor xenografts in immunodeficient mice, it possessed significant off-target affinity for the human ether-a-go-go-related gene protein (hERG Ki = 750 nM), thereby significantly limiting its potential for development. Herein, we disclose the rational and systematic modification of compound 2 to reduce the affinity for hERG while maintaining its affinity for and activity against DCN1. These studies led to the discovery of compound 110, which exhibited equivalent biochemical and cellular potency to 2, improved physicochemical properties, and increased selectivity relative to hERG.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"22 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218801","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

Centromere-Targeting Chimeras for Combating Cancer Drug Resistance 以着丝粒为靶点的嵌合体对抗癌症耐药性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-19 DOI: 10.1021/acs.jmedchem.6c01197

Dingpeng Zhang,Zhen Wang,William W. Feng,Wenyun Zhang,Xutong Xue,Yan Xiong,Xing Gao,Hiroyuki Inuzuka,Jeanelle Tsai,Jiaqi Li,Peiqiang Yan,Zhenbo Tu,Joao A. Paulo,H. Ümit Kaniskan,Antoine E. Karnoub,Pasi A. Jänne,Jian Jin,Wenyi Wei

{"title":"Centromere-Targeting Chimeras for Combating Cancer Drug Resistance","authors":"Dingpeng Zhang,Zhen Wang,William W. Feng,Wenyun Zhang,Xutong Xue,Yan Xiong,Xing Gao,Hiroyuki Inuzuka,Jeanelle Tsai,Jiaqi Li,Peiqiang Yan,Zhenbo Tu,Joao A. Paulo,H. Ümit Kaniskan,Antoine E. Karnoub,Pasi A. Jänne,Jian Jin,Wenyi Wei","doi":"10.1021/acs.jmedchem.6c01197","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01197","url":null,"abstract":"Centromere protein B (CENPB), the only sequence-specific DNA-binding protein at centromeres, maintains chromosomal stability and accurate mitotic segregation. Its overexpression in aggressive cancers is associated with aneuploidy and poor prognosis, yet CENPB remains therapeutically underexplored because direct inhibitors are unavailable. Here, we develop CENPB OligoTAC, a DNA-based PROTAC comprising a CENPB-binding oligodeoxynucleotide linked to an E3 ligase ligand. CENPB OligoTAC induces ubiquitination and proteasomal degradation of CENPB, disrupting centromere integrity, causing chromosome mis-segregation, and activating apoptosis. It shows potent activity in preclinical non-small cell lung cancer models resistant to first-, second-, and third-generation tyrosine kinase inhibitors, while exhibiting minimal cytotoxicity toward normal cells and good serum stability. In vivo, CENPB OligoTAC demonstrates favorable pharmacokinetics, good tolerability, and no significant hematological changes. By exploiting cancer cells’ dependence on centromeric stability, this platform offers a novel strategy for selectively targeting aneuploid malignancies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"7 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218802","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 a Pyrazine-2-Carboxamide Derivative as a Potent Plasmodium falciparum Inhibitor with Potential for Single-Dose Cure 吡嗪-2-羧酰胺衍生物作为恶性疟原虫有效抑制剂的发现，具有单剂量治愈的潜力

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-19 DOI: 10.1021/acs.jmedchem.6c01710

Vanessa M. Marx,Anne-Catherine Mata,Fumiaki Yokokawa,Thomas Kirrane,Richard Huang,Suresh B. Lakshminarayana,Jay Prakash Jain,Judith Straimer,W. Armand Guiguemde,Luying Pei,Upendra Kulkarni,Christopher J. Thompson,Johanna M. Jansen,Patrick S. Lee,Eric J. Martin,Valery R. Polyakov,Nicole Blaquiere,Alexander Burckle,Grace Waldron,Benjamin R. Taft,Erika L. Flannery,Hanna Schulz,Qumber H. Jafri,Katherine Chan,Erika Kim,Harry Cheung,Vida Ahyong,Changbok Lee,Catherine L. Jones,Christopher S. Lunde,Iñigo Angulo-Barturen,María Belén Jiménez-Díaz,Leyre Pernaute-Lau,Christian Scheurer,Sibylle Sax,Sergio Wittlin,Anna Caroline Campos Aguiar,Rafael Victorio Carvalho Guido,Dhelio B. Pereira,Philip J. Rosenthal,Roland A. Cooper,Kyra A. Schindler,David A. Fidock,Brice Campo,Simon F. Campbell,Thierry T. Diagana,Christopher R. Sarko

{"title":"Discovery of a Pyrazine-2-Carboxamide Derivative as a Potent Plasmodium falciparum Inhibitor with Potential for Single-Dose Cure","authors":"Vanessa M. Marx,Anne-Catherine Mata,Fumiaki Yokokawa,Thomas Kirrane,Richard Huang,Suresh B. Lakshminarayana,Jay Prakash Jain,Judith Straimer,W. Armand Guiguemde,Luying Pei,Upendra Kulkarni,Christopher J. Thompson,Johanna M. Jansen,Patrick S. Lee,Eric J. Martin,Valery R. Polyakov,Nicole Blaquiere,Alexander Burckle,Grace Waldron,Benjamin R. Taft,Erika L. Flannery,Hanna Schulz,Qumber H. Jafri,Katherine Chan,Erika Kim,Harry Cheung,Vida Ahyong,Changbok Lee,Catherine L. Jones,Christopher S. Lunde,Iñigo Angulo-Barturen,María Belén Jiménez-Díaz,Leyre Pernaute-Lau,Christian Scheurer,Sibylle Sax,Sergio Wittlin,Anna Caroline Campos Aguiar,Rafael Victorio Carvalho Guido,Dhelio B. Pereira,Philip J. Rosenthal,Roland A. Cooper,Kyra A. Schindler,David A. Fidock,Brice Campo,Simon F. Campbell,Thierry T. Diagana,Christopher R. Sarko","doi":"10.1021/acs.jmedchem.6c01710","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01710","url":null,"abstract":"Malaria remains a major cause of morbidity and mortality, particularly among young children, in endemic regions such as sub-Saharan Africa and Southeast Asia. Moreover, the emerging resistance of Plasmodium parasites to front-line therapeutics underscores the need for new blood-stage antimalarial drugs. Utilizing a Plasmodium falciparum (Pf) growth inhibition assay, we identified a novel pyrazine-2-carboxamide series. Lead optimization improved anti-plasmodial potency, metabolic stability, and reduced CYP2D6 inhibition risk, leading to the selection of IWY357 (1). A single dose of 100 mg per kg (mpk) is fully curative in a Pf-humanized severe combined immunodeficient mouse model (TADhuMouse®-Pfalc), and IWY357 (1) also exhibits a high barrier to resistance in drug selection studies. Given the significant potential to provide a curative therapy for uncomplicated malaria with short dosing regimens, either alone or in combination, IWY357 (1) was progressed through GLP toxicology studies into phase 1 clinical trials.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218804","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 Novel Small-Molecule Antagonist of the NOD1 Signaling Pathway as a Therapeutic Strategy for Acute Pancreatitis 新型小分子NOD1信号通路拮抗剂作为急性胰腺炎的治疗策略

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-18 DOI: 10.1021/acs.jmedchem.6c02155

Xinhua Liu,Dan Wang,Yuting Wang,Nan Zhang,Xiduan Wei,Shiping Fang,Shengtao Zhu,Yao Ma,Wenjun Yu,Gang Liu

引用次数: 0

De Novo Design of Multi-Mechanistic AIE Photosensitizer for Broad-Spectrum Bacterial Eradication 广谱杀菌用多机制AIE光敏剂的全新设计

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-18 DOI: 10.1021/acs.jmedchem.6c02325

Zhi-Hao Li,Yi-Qiong Sun,Daran Li,Kai-Wei Zhu,Shuya Chen,Luyang Xue,Xuehua Liu,Ruirui Li,Hongtao Kong,Yin-Chao Li,En Zhang

{"title":"De Novo\u0000 Design of Multi-Mechanistic AIE Photosensitizer for Broad-Spectrum Bacterial Eradication","authors":"Zhi-Hao Li,Yi-Qiong Sun,Daran Li,Kai-Wei Zhu,Shuya Chen,Luyang Xue,Xuehua Liu,Ruirui Li,Hongtao Kong,Yin-Chao Li,En Zhang","doi":"10.1021/acs.jmedchem.6c02325","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02325","url":null,"abstract":"Abstract Antibiotic resistance poses a serious threat to human health. Inspired by the clinical practice of employing drug combinations to achieve combined effects, we hypothesized that integrating multiple mechanisms into a single molecule could address drug-resistant bacterial infections. Based on a propeller-modification strategy and dual alkyl-chain engineering, we de novo designed and synthesized a C2-symmetric propeller-shaped aggregation-induced emission photosensitizer. After iterative screening, the optimized compound MeOTDP-2 exhibits broad-spectrum antibacterial activity, enabling efficient eradication of planktonic bacteria, drug-resistant strains, polymicrobial infections, biofilms, and persister cells, with no cellular invasiveness and negligible cytotoxicity. Mechanistic studies revealed that MeOTDP-2 achieves chemo-photodynamic combined antibacterial therapy by targeting and disrupting bacterial membranes and DNA, alongside light-mediated intracellular reactive oxygen species accumulation. Furthermore, in mouse models of MRSA-induced skin abscess and full-thickness skin wound infection, MeOTDP-2 demonstrated superior therapeutic efficacy to vancomycin. This strategy, integrating dual targeting with multiple mechanisms, offers new promise for overcoming bacterial resistance.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"11 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210246","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 Pentacyclic Triterpene Derivatives as Intestinal FXR Antagonists for Type 2 Diabetes 五环三萜衍生物作为2型糖尿病肠道FXR拮抗剂的设计、合成和生物学评价

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-18 DOI: 10.1021/acs.jmedchem.6c02247

Li Zhang,Pan Tang,Yun Xu,Cheng Cheng,Gaofeng Zhu,Lei Tang

引用次数: 0

Recent Advances in Peptide−Oligonucleotide Conjugates for Enhanced Therapeutic Efficacy 肽-寡核苷酸缀合物提高治疗效果的最新进展

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-18 DOI: 10.1021/acs.jmedchem.6c02803

Min An,Yuting Dai,Le Ma,Lu Yang,Jiahui Ma,Yangbing Li,Yaping Ma,Long Qin,Zhijian Han

{"title":"Recent Advances in Peptide−Oligonucleotide Conjugates for Enhanced Therapeutic Efficacy","authors":"Min An,Yuting Dai,Le Ma,Lu Yang,Jiahui Ma,Yangbing Li,Yaping Ma,Long Qin,Zhijian Han","doi":"10.1021/acs.jmedchem.6c02803","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02803","url":null,"abstract":"Oligonucleotide therapeutics have emerged as next-generation therapeutics. However, targeted delivery of oligonucleotides to extrahepatic tissues, such as skeletal and cardiac muscles and the central nervous system, at efficacious yet well-tolerated doses remain a major challenge for their clinical translation. Although antibody−oligonucleotide conjugates are promising for the treatment of genetic disorders, inadequate tissue penetration and immunogenicity have constrained their therapeutic efficacy. By combining the advantages of cell-penetrating peptides (CPPs) or cell-targeting peptides (CTPs) with those of oligonucleotides, peptide−oligonucleotide conjugates (POCs) display enhanced cellular uptake, endosomal escape, and extrahepatic delivery. The therapeutic efficacy of POC was increased through conjugation with CPPs, endosomal-escape peptides (EEPs), fusogenic peptides, nuclear localization signal peptides, or CTPs. In this perspective, innovative molecular designs such as multivalent, cyclic, and chimeric peptides, and combinations of CPPs and EEPs, were explored, highlighting key advancements in POC development and providing insights into future directions for the development of novel POCs.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"11 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210903","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

Ligands Targeting α9-Containing Nicotinic Acetylcholine Receptors: Structure−Activity Relationships and Therapeutic Potential in Neuropathic Pain 靶向α9-含烟碱乙酰胆碱受体的配体：结构-活性关系和神经性疼痛的治疗潜力

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-18 DOI: 10.1021/acs.jmedchem.6c01450

Megan J. Jurek,Christian J. Peters,Andrew P. Riley

引用次数: 0