Journal of Medicinal Chemistry最新文献

{"title":"Novltex: A New Class of Antibiotics with Potent Activity against Multidrug-Resistant Bacterial Pathogens─Design, Synthesis, and Biological Evaluation","authors":"Esra Malkawi,&nbsp;, ,&nbsp;Anish Parmar,&nbsp;, ,&nbsp;Sanjit Das,&nbsp;, ,&nbsp;Enas Newire,&nbsp;, ,&nbsp;Charlotte M. Jones,&nbsp;, ,&nbsp;Kate A. Morrison,&nbsp;, ,&nbsp;Milandip Karak,&nbsp;, ,&nbsp;Frédéric Blanc,&nbsp;, ,&nbsp;Nicholas Harper,&nbsp;, ,&nbsp;Rajamani Lakshminarayanan,&nbsp;, ,&nbsp;Zhi Sheng Poh,&nbsp;, ,&nbsp;Navin K. Verma,&nbsp;, ,&nbsp;Jennifer Unsworth,&nbsp;, ,&nbsp;Dallas E. Hughes,&nbsp;, ,&nbsp;Losee Lucy Ling,&nbsp;, ,&nbsp;Stephen A. Cochrane,&nbsp;, ,&nbsp;William Hope,&nbsp;, and ,&nbsp;Ishwar Singh*,&nbsp;","doi":"10.1021/acs.jmedchem.5c01193","DOIUrl":"10.1021/acs.jmedchem.5c01193","url":null,"abstract":"<p >Increasing spread of multidrug-resistant (MDR) bacteria demands antibiotics that combine potent activity with scalable synthesis. Novo29 (clovibactin) is promising but suffers from low yield (1%), dependence on costly and noncommercial <span>d</span>-hydroxy-asparagine (<span>d</span>-Hyn₅), and lengthy syntheses. We report “Novltex”, a novel class of antibiotic that fuses the Leu₁₀-teixobactin macrocycle to the Novo29 N-terminus tail, replacing <span>d</span>-Hyn₅ with inexpensive threonine. Our efficient synthesis delivers 30% yield with faster coupling cycles (∼10 min), enabling rapid and low-cost scale-up. A 16-member analogue library systematically probing amino-acid configuration identified analogue <b>4</b> (<span>d</span>-Leu₂) as the initial lead, informing the rational design of analogue <b>12</b> (<span>d</span>-cyclohexylalanine₂). Analogue 12 displays potent antibacterial activity (minimum inhibitory concentration (MIC) 0.12–0.5 μg/mL) against World Health Organization (WHO)-priority pathogens, including methicillin-resistant <i>Staphylococcus aureus (</i>MRSA) and <i>Enterococcus faecium</i>, surpassing several licensed antibiotics while maintaining an excellent safety profile. Lipid II-binding assays confirm the conservation of the parent mechanism. Novltex, therefore, offers a practical, high-yielding, and cost-efficient platform for the development of next-generation antibiotics targeting MDR infections.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19143–19152"},"PeriodicalIF":6.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5c01193","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C-Branched Iminosugars as Selective Pharmacological Chaperones of Lysosomal α-Glucosidase for the Treatment of Pompe Disease","authors":"Anaïs Vieira Da Cruz,&nbsp;, ,&nbsp;Valentine Perraudin,&nbsp;, ,&nbsp;Nadia Minopoli,&nbsp;, ,&nbsp;Roberta Iacono,&nbsp;, ,&nbsp;Véronique Roig-Zamboni,&nbsp;, ,&nbsp;Andrea Bossio,&nbsp;, ,&nbsp;Salia Tangara,&nbsp;, ,&nbsp;Martine Fayolle,&nbsp;, ,&nbsp;Alice Kanazawa,&nbsp;, ,&nbsp;Christian Philouze,&nbsp;, ,&nbsp;Antonietta Tarallo,&nbsp;, ,&nbsp;Jurriaan J. A. Heming,&nbsp;, ,&nbsp;Marta Artola,&nbsp;, ,&nbsp;Jean-Bernard Behr,&nbsp;, ,&nbsp;Herman S. Overkleeft,&nbsp;, ,&nbsp;Marco Moracci*,&nbsp;, ,&nbsp;Gerlind Sulzenbacher*,&nbsp;, ,&nbsp;Giancarlo Parenti*,&nbsp;, and ,&nbsp;Sandrine Py*,&nbsp;","doi":"10.1021/acs.jmedchem.5c01349","DOIUrl":"10.1021/acs.jmedchem.5c01349","url":null,"abstract":"<p >We report herein the design and synthesis of a series of 5-<i>C</i>-alkyldeoxynojirimycins from <span>l</span>-sorbose, through an efficient and scalable method amenable to preparing a large variety of analogues. The interaction of this class of compounds with human acid α-glucosidase (GAA), the genetically defective enzyme in patients suffering from Pompe disease, was investigated to identify pharmacological chaperones exhibiting high selectivity for this enzyme. Crystallographic analyses provided a rationale for their binding mode to GAA and chaperone activity. The effects of 5-<i>C</i>-phenethyl-DNJ (<b>4c</b>) were evaluated on GAA activity enhancement in cells from Pompe disease patients and <i>in vivo</i> in GAA-KO mice. The significant increase of GAA activity in the presence of <b>4c</b> in various tissues, particularly in the diaphragm, encourages further studies on this class of small molecules toward developing clinical drugs. Their chaperone activity and excellent selectivity may offer potential benefits over the current treatments for Pompe disease.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19269–19286"},"PeriodicalIF":6.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058912","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}

{"title":"Exploiting Avidity Effects for the Discovery of Low Affinity Protein-Binding Fragments","authors":"Isuru M. Jayalath,&nbsp;, ,&nbsp;Donella Beckwith,&nbsp;, ,&nbsp;Jihyeon Yoon,&nbsp;, ,&nbsp;Xingui Liu,&nbsp;, and ,&nbsp;Thomas Kodadek*,&nbsp;","doi":"10.1021/acs.jmedchem.5c01742","DOIUrl":"10.1021/acs.jmedchem.5c01742","url":null,"abstract":"<p >Fragment-based drug discovery (FBDD) is a powerful approach to the development of pharmaceuticals and probe molecules and there is broad interest in the development of new platforms for their discovery. Here, we introduce a workflow in which low molecular weight organic molecules displayed on the surface of TentaGel beads are exposed to a multimeric, fluorescently labeled target protein. Using tetrameric or dimeric protein targets, we show that beads that display even weak ligands (<i>K</i>_Ds in the high μM to low mM range) stably capture the protein due to avidity effects, thus allowing a simple “pull-down” protocol to be employed for fragment discovery. We also demonstrate that the platform is capable of supporting a “fragment growth” screen, which is a typical strategy to advance a fragment to a higher-affinity lead molecule. This platform is inexpensive and requires no specialized infrastructure.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19521–19535"},"PeriodicalIF":6.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058910","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}

{"title":"10-Hydroxycamptothecin-Loaded Hollow Mesoporous Polydopamine Modified with ANGPT2-Specific Peptide for Gastric Cancer-Targeted Therapy","authors":"Haidong Tian,&nbsp;, ,&nbsp;LanLan Lin,&nbsp;, ,&nbsp;Huijun Guo,&nbsp;, ,&nbsp;Jiadi Liu,&nbsp;, ,&nbsp;Rong Gan,&nbsp;, ,&nbsp;Qiyue Zhang,&nbsp;, ,&nbsp;Duling Xu,&nbsp;, and ,&nbsp;Hongyan Li*,&nbsp;","doi":"10.1021/acs.jmedchem.5c01330","DOIUrl":"10.1021/acs.jmedchem.5c01330","url":null,"abstract":"<p >The side effects of hydroxycamptothecin (HCPT) limit its clinical application in antitumor. The surface of hollow mesoporous polydopamine (HMPDA) was modified with the ANGPT2-specific peptide GSFIHSVPRH (GSF), followed by loading HCPT and indocyanine green (ICG) to form a drug-delivery system (ICG-GSF-HMPDA@HCPT). The morphology, particle size, HCPT loading capacity, and HCPT-release properties were characterized. The biocompatibility and antitumor efficacy of the delivery system were validated through in vitro and in vivo experiments. Micropositron emission tomography (PET)/computed tomography (CT) imaging showed that ⁶⁸Ga-labeled GSF accumulated in the xenograft, and the targeting of GSF toward gastric cancer was confirmed. ICG-GSF-HMPDA@HCPT inhibited cell viability, colony formation, cell invasion, and migration of HGC-27 cells and showed a better suppression of xenograft development than HMPDA@HCPT. Furthermore, blood biochemical assays showed that ICG-GSF-HMPDA@HCPT exhibited favorable biosafety. Thus, the HCPT-loaded HMPDA modified with the ANGPT2-specific peptide was successfully constructed and served as a potent delivery for GC-targeted therapy.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19673–19687"},"PeriodicalIF":6.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059747","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}

{"title":"Correction to “Design and SAR Analysis of Phenylboronic Acid-Based Inhibitors for Sensitizing KPC-2-Producing Klebsiella pneumoniae to β-Lactam Antibiotics”","authors":"Mangal Singh,&nbsp;, ,&nbsp;Marc Boomgaren,&nbsp;, ,&nbsp;Perwez Bakht,&nbsp;, ,&nbsp;Patrick Ihle,&nbsp;, ,&nbsp;Hanna-Kirsti S. Leiros,&nbsp;, ,&nbsp;Annette Bayer*,&nbsp;, and ,&nbsp;Ranjana Pathania*,&nbsp;","doi":"10.1021/acs.jmedchem.5c02500","DOIUrl":"10.1021/acs.jmedchem.5c02500","url":null,"abstract":"","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19791"},"PeriodicalIF":6.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068650","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}

{"title":"Exceptionally Potent Chiral Anandamide Analogs","authors":"Markos-Orestis Georgiadis, Elena Ferreras, Lipin Ji, Luana Assis Ferreira, John Hainline, Fei Tong, Vuong Q. Dang, Alexandra Faragher, Anastasiia V. Sadybekov, Laura M. Bohn, Vsevolod Katritch, Andrea G. Hohmann, Alexandros Makriyannis, Spyros P. Nikas","doi":"10.1021/acs.jmedchem.5c02030","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02030","url":null,"abstract":"We recently reported an innovative design approach that allowed us to obtain potent endocannabinoids with enhanced metabolic stability. Our design is characterized by the incorporation of chiral centers within the endocannabinoid prototypes N-arachidonoylethanolamide and 2-arachidonoylglycerol. Work on N-arachidonoylethanolamide led to the identification of the first-generation lead analog (R)-N-(1-Methyl-2-hydroxyethyl)-13-(S)-methyl-arachidonamide (AMG315). Here, we synthesized a series of tail-modified AMG315 analogs to further optimize this novel chemotype for cannabinoid receptor binding affinity and potency. Our advanced molecule, namely, 20,20,20-trifluoro-(R)-N-(1-methyl-2-hydroxyethyl)-13-(S)-methyl-arachidonamide (AM12814, 12), is the first endocannabinoid analogue exhibiting unprecedented affinity for both the CB1 and CB2 receptors. In further in vitro functional characterization, 12 behaves as a potent, partial CB1 and CB2 agonist. Our SAR results are supported by docking studies of 12 on the crystal structures of cannabinoid receptors, while when tested in vivo, 12 behaves as a very potent and efficacious CB1 agonist. This analogue will serve as a unique endocannabinoid probe.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"15 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059746","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}

{"title":"Glycoconjugation of Quinoline as an Effective Strategy for Selective Inhibition of mTORC1","authors":"Subhadeep Palit,&nbsp;, ,&nbsp;Tanusree Das,&nbsp;, ,&nbsp;Bhim Majhi,&nbsp;, ,&nbsp;Partha Chakrabarti*,&nbsp;, and ,&nbsp;Sanjay Dutta*,&nbsp;","doi":"10.1021/acs.jmedchem.5c01139","DOIUrl":"10.1021/acs.jmedchem.5c01139","url":null,"abstract":"<p >The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that exists as mTORC1/2 complexes and regulates crucial cellular metabolic processes. Dysregulation of mTOR signaling is implicated in numerous chronic diseases. Rapalogs display limited clinical applications as selective mTORC1 inhibitors due to adverse metabolic and immunological effects arising from off-target inhibition of mTORC2, thereby warranting newer selective mTORC1 inhibitors. Herein, we have developed quinoline glycoconjugates that exhibit potent and selective mTORC1 inhibition in both in vitro and in vivo murine models. Our designed compounds feature a C-6 functionalized quinoline core with a C-3 ethoxypropyne handle, conjugated to mono- and bisglyco ligands via a triazole linker using click chemistry. Lead compound <b>TCG3</b> reduces cellular lipid accumulation and induces autophagy, with minimal or no cytotoxicity. These findings support <b>TCG3</b> as a promising selective mTORC1 inhibitor with potential therapeutic applications and highlight the effectiveness of glycoconjugation in fine-tuning selectivity and cytotoxicity.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19041–19061"},"PeriodicalIF":6.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058911","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}

{"title":"Discovery of Potent and Selective Pyrrolo[2,3-d]Pyrimidine-Based Aurora A Inhibitors with Demonstrated Efficacy against Patient-Derived Gastric Cancer Organoids","authors":"Rong Zhang,&nbsp;, ,&nbsp;Tao Yu,&nbsp;, ,&nbsp;Manzhan Zhang,&nbsp;, ,&nbsp;Jiatong Li,&nbsp;, ,&nbsp;Ao Gu,&nbsp;, ,&nbsp;Muerzhate Aimaiti,&nbsp;, ,&nbsp;Shiliang Li,&nbsp;, ,&nbsp;Huan He*,&nbsp;, ,&nbsp;Yingbin Liu*,&nbsp;, and ,&nbsp;Honglin Li*,&nbsp;","doi":"10.1021/acs.jmedchem.5c01886","DOIUrl":"10.1021/acs.jmedchem.5c01886","url":null,"abstract":"<p >Aurora A kinase, a key regulator of mitosis, has emerged as a promising therapeutic target for gastric cancer. However, challenges related to selectivity and resistance highlight the urgent need for novel Aurora A inhibitors with improved profiles. In this study, we rationally designed and synthesized a series of pyrrolo[2,3-<i>d</i>]pyrimidine-based Aurora A inhibitors via scaffold hopping and structural optimization of Alisertib. Among them, compound <b>11</b> demonstrated potent Aurora A inhibitory activity (IC₅₀ = 0.74 nM) and improved selectivity over Aurora B compared to Alisertib. It also exhibited strong antiproliferative effects in gastric cancer cell lines and superior efficacy in patient-derived gastric cancer organoids (IC₅₀ = 3.5 μM), outperforming Alisertib. These findings suggest that compound <b>11</b> is a highly potent and selective Aurora A inhibitor with significant therapeutic potential for gastric cancer treatment.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19607–19625"},"PeriodicalIF":6.8,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058913","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}

{"title":"Discovery of 3g as an Orally Bioavailable, TIR Domain Selective, and Potent MyD88 Inhibitor for the Treatment of Acute Lung Injury","authors":"Pan Chen,&nbsp;, ,&nbsp;Ke Dong,&nbsp;, ,&nbsp;Luxiao Zhu,&nbsp;, ,&nbsp;Nan Huang,&nbsp;, ,&nbsp;Kaixin Zhang,&nbsp;, ,&nbsp;Yuehua Lv,&nbsp;, ,&nbsp;Miao Jiang,&nbsp;, ,&nbsp;Qi Chen,&nbsp;, ,&nbsp;Yu Zou,&nbsp;, ,&nbsp;Zhichao Chen,&nbsp;, ,&nbsp;Mi Guo,&nbsp;, ,&nbsp;Zhiwei Zheng,&nbsp;, ,&nbsp;Chenhui Sun,&nbsp;, ,&nbsp;Young-Chang Cho*,&nbsp;, ,&nbsp;Guang Liang*,&nbsp;, and ,&nbsp;Qidong Tang*,&nbsp;","doi":"10.1021/acs.jmedchem.5c01786","DOIUrl":"10.1021/acs.jmedchem.5c01786","url":null,"abstract":"<p >Myeloid differentiation factor 88 (MyD88) plays a pivotal role in the inflammatory response. However, the number of MyD88 inhibitors is limited, and the effectiveness of current inhibitors is constrained, hindering the progress of clinical research. Herein, thirty-nine novel MyD88 inhibitors were developed based on our previously discovered lead compound <b>c17</b>, and the potent compound <b>3g</b> was identified using ELISA and DSF assays. Compound <b>3g</b> specifically and selectively targets the TIR domain of MyD88 rather than its DD domain, thereby preventing MyD88 self-polymerization and interaction with TLRs, which suppresses the activation of MAPK and NF-κB pathways. <b>3g</b> exhibits a bioavailability of 63% and shows no substantial in vivo toxicity, maintaining notable stability in plasma and digestive juices. Moreover, <b>3g</b> demonstrated significant anti-inflammatory efficacy and effectively mitigated ALI symptoms in CLP and LPS-induced ALI models. These data indicate that <b>3g</b> possesses considerable potential as a MyD88 inhibitor for the treatment of ALI.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19626–19644"},"PeriodicalIF":6.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035770","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}

{"title":"Revealing GRP75-Mediated Mitochondrial Stability That Promotes Breast Cancer Survival through Subcellular Anchoring of 70 kDa Heat Shock Protein Inhibitors","authors":"Maojun Jiang,&nbsp;, ,&nbsp;Yang Song,&nbsp;, ,&nbsp;Hong Zhang,&nbsp;, ,&nbsp;Fangkui Yin,&nbsp;, ,&nbsp;Zhiyuan Hu,&nbsp;, ,&nbsp;Zheming Wang,&nbsp;, ,&nbsp;Yitong Li,&nbsp;, ,&nbsp;Zihan Wang,&nbsp;, ,&nbsp;Yanxin Zhang,&nbsp;, ,&nbsp;Siyao Wang,&nbsp;, ,&nbsp;Teng Yi,&nbsp;, ,&nbsp;Ke Wang,&nbsp;, ,&nbsp;Siting Feng,&nbsp;, ,&nbsp;Zixuan Yang,&nbsp;, ,&nbsp;Xiuwen Fan,&nbsp;, ,&nbsp;Haoxin Lun,&nbsp;, ,&nbsp;Ting Song,&nbsp;, ,&nbsp;Ziqian Wang*,&nbsp;, and ,&nbsp;Zhichao Zhang*,&nbsp;","doi":"10.1021/acs.jmedchem.5c01279","DOIUrl":"10.1021/acs.jmedchem.5c01279","url":null,"abstract":"<p >The 70 kDa heat shock protein (HSP70) isoforms play distinct roles in cancer, but their structural similarity limits isoform-specific inhibition. Here, we modified nonselective HSP70 inhibitor <b>S1g-10</b> via a subcellular anchoring strategy to generate compounds <b>5</b> and <b>8</b>, which selectively target mitochondrial-localized GRP75 and ER-localized GRP78, respectively. Both compounds modulated their intended targets in vivo. Additionally, GRP75, but not GRP78, was identified as a key regulator of mitochondrial membrane stability in breast cancer cells and maintains the stemness of breast cancer stem cells (BCSCs). Compared with normal cells, compound <b>5</b> exhibited selective toxicity against breast cancer cells and effectively suppressed the properties of BCSCs. This study provides novel chemical probes for studying specific isoforms of HSP70 and introduces a strategy to develop GRP75-targeted therapeutics for breast cancer.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19169–19183"},"PeriodicalIF":6.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035771","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}