Polθ, a key enzyme mediating microhomology-mediated end joining (MMEJ), is overexpressed in multiple human cancers and represents a promising therapeutic target, particularly in tumors with homologous recombination (HR) deficiency. Herein, we report the discovery and optimization of a novel series of Polθ polymerase (Polθ-pol) inhibitors featuring an arylalkyne scaffold, which extends into a peripheral channel within the polymerase domain to enhance target engagement. Among the synthesized compounds, compound 20 exhibited potent inhibitory activity against Polθ-pol at a nanomolar level (IC50 = 1.3 nM), along with antiproliferative activity against the HR-deficient cancer cell lines, such as MDA-MB-436, Capan-1, and DLD-1 (BRCA2-/-). Moreover, compound 20 demonstrated favorable pharmacokinetic properties, with oral bioavailability values of 103.36% in mice and 63.71% in rats, respectively. In an MDA-MB-436 xenograft model, compound 20 significantly suppressed tumor growth without evident toxicity. These findings underscore the arylalkyne scaffold as a highly promising strategy for the development of orally active Polθ-targeted therapeutics.
{"title":"Discovery of Novel Orally Bioavailable Polθ Inhibitors with Arylalkyne Scaffolds for Targeting HR-Deficient Cancers.","authors":"Jinyang Zhang,Xiaomeng Sun,Qichen Zhou,Yingying Wei,Biao Chen,Junhui Jiao,Yu Du,Shepherd Wufoyrwoth,Haoze Chi,Yi Yang,Ping Wei,Yungen Xu,Yi Zou,Qihua Zhu","doi":"10.1021/acs.jmedchem.5c01977","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01977","url":null,"abstract":"Polθ, a key enzyme mediating microhomology-mediated end joining (MMEJ), is overexpressed in multiple human cancers and represents a promising therapeutic target, particularly in tumors with homologous recombination (HR) deficiency. Herein, we report the discovery and optimization of a novel series of Polθ polymerase (Polθ-pol) inhibitors featuring an arylalkyne scaffold, which extends into a peripheral channel within the polymerase domain to enhance target engagement. Among the synthesized compounds, compound 20 exhibited potent inhibitory activity against Polθ-pol at a nanomolar level (IC50 = 1.3 nM), along with antiproliferative activity against the HR-deficient cancer cell lines, such as MDA-MB-436, Capan-1, and DLD-1 (BRCA2-/-). Moreover, compound 20 demonstrated favorable pharmacokinetic properties, with oral bioavailability values of 103.36% in mice and 63.71% in rats, respectively. In an MDA-MB-436 xenograft model, compound 20 significantly suppressed tumor growth without evident toxicity. These findings underscore the arylalkyne scaffold as a highly promising strategy for the development of orally active Polθ-targeted therapeutics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"52 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073241","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}
Pub Date : 2026-01-29DOI: 10.1021/acs.jmedchem.5c03032
Rensong Sun, Zhihao Chen, Ruitao Yang, Yuan Liang, Wen Sun, Engin U. Akkaya, Lei Wang
Tumor microenvironment not only compromises the therapeutic efficacy of chemotherapy but also weakens chemotherapy-induced immunogenic cell death. Herein, we report novel platinumIV prodrugs that integrate two clinically approved drugs with different but complementary mechanisms, where cisplatin provides tumor cytotoxicity while the pirfenidone analogue contributes to tumor microenvironment modulation. In vitro evaluations suggested their superior anticancer activity, improved resistance profiles, and favorable selectivity across multiple cancer cell lines. Mechanistic studies revealed that they not only depleted intracellular glutathione and suppressed P-gp expression but also remodeled the tumor microenvironment through multiple actions. Notably, they triggered the release of damage-associated molecular patterns (DAMPs), promoted dendritic cell maturation, and induced strong immunogenic cell death despite that cisplatin is unable to induce an immunological response. In vivo studies further confirmed their antitumor activity (3.3-fold tumor inhibition compared to cisplatin) and favorable safety profile (64% weight loss by cisplatin, none with platinumIV complexes).
{"title":"PlatinumIV Complex Enabling Multiple and Potent Tumor Microenvironment Remodeling for Cancer Chemo-Immunotherapy","authors":"Rensong Sun, Zhihao Chen, Ruitao Yang, Yuan Liang, Wen Sun, Engin U. Akkaya, Lei Wang","doi":"10.1021/acs.jmedchem.5c03032","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03032","url":null,"abstract":"Tumor microenvironment not only compromises the therapeutic efficacy of chemotherapy but also weakens chemotherapy-induced immunogenic cell death. Herein, we report novel platinum<sup>IV</sup> prodrugs that integrate two clinically approved drugs with different but complementary mechanisms, where cisplatin provides tumor cytotoxicity while the pirfenidone analogue contributes to tumor microenvironment modulation. In vitro evaluations suggested their superior anticancer activity, improved resistance profiles, and favorable selectivity across multiple cancer cell lines. Mechanistic studies revealed that they not only depleted intracellular glutathione and suppressed P-gp expression but also remodeled the tumor microenvironment through multiple actions. Notably, they triggered the release of damage-associated molecular patterns (DAMPs), promoted dendritic cell maturation, and induced strong immunogenic cell death despite that cisplatin is unable to induce an immunological response. In vivo studies further confirmed their antitumor activity (3.3-fold tumor inhibition compared to cisplatin) and favorable safety profile (64% weight loss by cisplatin, none with platinum<sup>IV</sup> complexes).","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146070668","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}
Pub Date : 2026-01-29DOI: 10.1021/acs.jmedchem.5c01426
Adi Suwandi,Jianwen Jin,Yichao Zhao,Ramesh Mudududdla,Yi Sing Gee,Girdhar Singh Deora,Yuxin Sun,Heping Wei,Fei Huang,Jin-Shu He,Amee J George,Stefan J Hermans,David J Leaver,Michael W Parker,Jonathan B Baell
All lysine acetyltransferases (KATs) modulate biological outcomes through the acetylation of lysine side-chain amino groups facilitated by acetyl coenzyme A (AcCoA). KAT6A belongs to the class of MYST domain histone acetyltransferases (HATs), which had been regarded as undruggable. The first on-target KAT6A inhibitors with in vivo activity were reported in 2018, catalyzing intense industry interest in this enzyme as an oncology target. In this study, we experimentally evaluated representative KAT6A inhibitor chemotypes through resynthesis and comparative biochemical assays, cellular assays, and structural biology. We outline the recent history of each KAT6A inhibitor chemotype discovery, including SAR for potency, selectivity, and cellular activity. We extensively benchmark key compounds from each chemotype, augmented by new acylsulfonohydrazide analogues and a novel fused [1,2,4]thiadiazine KAT6A inhibitor subclass, which we report here for the first time, along with co-crystal structures. Additionally, we report on the in vivo activity, pharmacokinetics, and toxicology profiles of these inhibitors.
{"title":"Biological Activity and Structural Biology of Current KAT6A Inhibitor Chemotypes.","authors":"Adi Suwandi,Jianwen Jin,Yichao Zhao,Ramesh Mudududdla,Yi Sing Gee,Girdhar Singh Deora,Yuxin Sun,Heping Wei,Fei Huang,Jin-Shu He,Amee J George,Stefan J Hermans,David J Leaver,Michael W Parker,Jonathan B Baell","doi":"10.1021/acs.jmedchem.5c01426","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01426","url":null,"abstract":"All lysine acetyltransferases (KATs) modulate biological outcomes through the acetylation of lysine side-chain amino groups facilitated by acetyl coenzyme A (AcCoA). KAT6A belongs to the class of MYST domain histone acetyltransferases (HATs), which had been regarded as undruggable. The first on-target KAT6A inhibitors with in vivo activity were reported in 2018, catalyzing intense industry interest in this enzyme as an oncology target. In this study, we experimentally evaluated representative KAT6A inhibitor chemotypes through resynthesis and comparative biochemical assays, cellular assays, and structural biology. We outline the recent history of each KAT6A inhibitor chemotype discovery, including SAR for potency, selectivity, and cellular activity. We extensively benchmark key compounds from each chemotype, augmented by new acylsulfonohydrazide analogues and a novel fused [1,2,4]thiadiazine KAT6A inhibitor subclass, which we report here for the first time, along with co-crystal structures. Additionally, we report on the in vivo activity, pharmacokinetics, and toxicology profiles of these inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"42 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073242","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}
Histone deacetylase (HDAC) inhibitors exert anticancer effects through epigenetic regulation. Developing HDAC inhibitors with different chemical types represents a promising anticancer treatment strategy. Herein, we established an enhanced comprehensive computational pipeline to identify tertiary benzenesulfonanilide-based HDAC inhibitor lead compounds and elucidate activity differences among derivatives based on electronic properties. Highly active HIT211504993 is a potent inhibitor selective for HDAC6 (IC50 = 0.07 μM) over HDAC2 and HDAC4. HIT211504993 (20 μM) suppresses colon cancer cell proliferation and induces apoptosis in vitro and significantly inhibits tumor growth (50 mg/kg, 77%) in an HCT-8 xenograft model, comparable to SAHA (50 mg/kg, 81%). Mechanistically, HIT211504993 inhibits Myc-driven tumorigenesis by promoting nucleocytoplasmic acetylation and modulating p53, cell-cycle, and Wnt/β-catenin signaling. The investigation of antitumor activity and its mechanism of action provides a theoretical basis for the development of the next-generation benzenesulfonanilide HDAC inhibitors.
{"title":"Discovery of Tertiary Benzenesulfonanilide Chemotypes as HDAC Inhibitors via Multistrategy In Silico and Biological Evaluation for Colon Cancer Therapy.","authors":"Denghui Gao,Shuo Yang,Mingyue Li,Lihua Zheng,Luguo Sun,Yongli Bao,Zhenbo Song,Yanxin Huang","doi":"10.1021/acs.jmedchem.5c03634","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03634","url":null,"abstract":"Histone deacetylase (HDAC) inhibitors exert anticancer effects through epigenetic regulation. Developing HDAC inhibitors with different chemical types represents a promising anticancer treatment strategy. Herein, we established an enhanced comprehensive computational pipeline to identify tertiary benzenesulfonanilide-based HDAC inhibitor lead compounds and elucidate activity differences among derivatives based on electronic properties. Highly active HIT211504993 is a potent inhibitor selective for HDAC6 (IC50 = 0.07 μM) over HDAC2 and HDAC4. HIT211504993 (20 μM) suppresses colon cancer cell proliferation and induces apoptosis in vitro and significantly inhibits tumor growth (50 mg/kg, 77%) in an HCT-8 xenograft model, comparable to SAHA (50 mg/kg, 81%). Mechanistically, HIT211504993 inhibits Myc-driven tumorigenesis by promoting nucleocytoplasmic acetylation and modulating p53, cell-cycle, and Wnt/β-catenin signaling. The investigation of antitumor activity and its mechanism of action provides a theoretical basis for the development of the next-generation benzenesulfonanilide HDAC inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"483 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073243","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}
Pub Date : 2026-01-28DOI: 10.1021/acs.jmedchem.5c02018
Dipak T Walunj,Bocheng Wu,Jeremiah O Olugbami,Alexis Johnston,Ryan Kern,Travis J Nelson,Benjamin H Peer,Justin Keener,Peixian He,Nathaniel A Hathaway,Adegboyega K Oyelere
Histamine receptor H1 (HRH1) is upregulated within the tumor microenvironment, where it supports tumorigenesis by several mechanisms. Cationic amphiphilic drugs targeting HRH1 are currently under investigation for repurposing into cancer therapy. Herein, we showed that Clemizole, a first-generation HRH1 antagonist that selectively accumulates within the liver, could be used as a template to design small-molecule epigenetic modifiers targeting histone deacetylases (HDACs) and histone lysine demethylases (KDMs). The resulting HDACi and KDMi have midnanomolar to single-digit micromolar IC50s and potency enhancement of 15-105 folds relative to Clemizole. Several of these compounds elicited cancer cell line-dependent cytotoxicity. Representative lead KDMi, Cle-C6K, and Cle-C8K caused transcriptome-level perturbations favoring cell cycle inhibition and apoptosis. Moreover, Cle-C8K is nontoxic and selectively accumulated in the liver of C57BL/6 mice. Collectively, our data reveal that Clemizole could be repositioned to design liver tissue-accumulating epigenetic-modifying small molecules as potential targeted antiliver cancer agents.
{"title":"Repositioning Antihistamine for Cancer Therapy: Clemizole as a Template for the Design of Liver Tissue-Targeting Epigenetic-Modifying Agents.","authors":"Dipak T Walunj,Bocheng Wu,Jeremiah O Olugbami,Alexis Johnston,Ryan Kern,Travis J Nelson,Benjamin H Peer,Justin Keener,Peixian He,Nathaniel A Hathaway,Adegboyega K Oyelere","doi":"10.1021/acs.jmedchem.5c02018","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02018","url":null,"abstract":"Histamine receptor H1 (HRH1) is upregulated within the tumor microenvironment, where it supports tumorigenesis by several mechanisms. Cationic amphiphilic drugs targeting HRH1 are currently under investigation for repurposing into cancer therapy. Herein, we showed that Clemizole, a first-generation HRH1 antagonist that selectively accumulates within the liver, could be used as a template to design small-molecule epigenetic modifiers targeting histone deacetylases (HDACs) and histone lysine demethylases (KDMs). The resulting HDACi and KDMi have midnanomolar to single-digit micromolar IC50s and potency enhancement of 15-105 folds relative to Clemizole. Several of these compounds elicited cancer cell line-dependent cytotoxicity. Representative lead KDMi, Cle-C6K, and Cle-C8K caused transcriptome-level perturbations favoring cell cycle inhibition and apoptosis. Moreover, Cle-C8K is nontoxic and selectively accumulated in the liver of C57BL/6 mice. Collectively, our data reveal that Clemizole could be repositioned to design liver tissue-accumulating epigenetic-modifying small molecules as potential targeted antiliver cancer agents.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"74 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056809","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}
Pub Date : 2026-01-28DOI: 10.1021/acs.jmedchem.5c02718
Emily C Hank,Loris Knümann,Úrsula López-García,Arthur Kardanov,Vasily Morozov,Georg Höfner,Daniel Merk
The transcription factor tailless homologue (TLX, NR2E1) maintains persistence of neural stem cells (NSCs) in a proliferating, undifferentiated state, thereby controlling NSC homeostasis and enabling neurogenesis. TLX is responsive to small-molecule ligands, offering potential access to new neuroprotective treatments, but TLX ligands are very rare. Here, we used a drug fragment screening hit as lead to develop TLX modulators and identified substructures tuning activity between agonism and inverse agonism. Structural optimization provided potent TLX activating and inhibiting fragment ligands with validated binding and favorable ligand efficiency for structural extension.
{"title":"Systematic Optimization of Fragment TLX Ligands toward Agonism and Inverse Agonism.","authors":"Emily C Hank,Loris Knümann,Úrsula López-García,Arthur Kardanov,Vasily Morozov,Georg Höfner,Daniel Merk","doi":"10.1021/acs.jmedchem.5c02718","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02718","url":null,"abstract":"The transcription factor tailless homologue (TLX, NR2E1) maintains persistence of neural stem cells (NSCs) in a proliferating, undifferentiated state, thereby controlling NSC homeostasis and enabling neurogenesis. TLX is responsive to small-molecule ligands, offering potential access to new neuroprotective treatments, but TLX ligands are very rare. Here, we used a drug fragment screening hit as lead to develop TLX modulators and identified substructures tuning activity between agonism and inverse agonism. Structural optimization provided potent TLX activating and inhibiting fragment ligands with validated binding and favorable ligand efficiency for structural extension.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"42 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056800","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}
Pub Date : 2026-01-28DOI: 10.1021/acs.jmedchem.5c02354
Rebecka Isaksson, Eve M. Carter, Charlotte K. Hind, J. Mark Sutton, Hazel Rudgyard, Adam H. Roberts, Christopher W. Moon, Yinuo Wang, Todd Group Researchers, Sandra Codony, Antón L. Martínez, Joanna Bacon, Matthew H. Todd
Academic drug discovery laboratories tend to accumulate collections of compounds with great potential value that merely reside in fridges and freezers. Cross screening these libraries against alternative targets holds significant potential for uncovering novel hits, but in the academic setting compound collections are rarely used, and shared, in this way. We present a short guide for collecting small molecules not being actively pursued in group projects (which we term “idlers”) to establish an open compound library. We describe how a diverse subset of this library was screened against a panel of pathogens, with the resulting data made publicly available. We hope to encourage other academic groups to develop and share their own libraries of idlers, thereby maximizing the utility of existing resources, enabling new insights, and catalyzing novel research directions through open science.
{"title":"Idler Compounds: A Simple Protocol for Openly Sharing Fridge Contents for Cross-Screening","authors":"Rebecka Isaksson, Eve M. Carter, Charlotte K. Hind, J. Mark Sutton, Hazel Rudgyard, Adam H. Roberts, Christopher W. Moon, Yinuo Wang, Todd Group Researchers, Sandra Codony, Antón L. Martínez, Joanna Bacon, Matthew H. Todd","doi":"10.1021/acs.jmedchem.5c02354","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02354","url":null,"abstract":"Academic drug discovery laboratories tend to accumulate collections of compounds with great potential value that merely reside in fridges and freezers. Cross screening these libraries against alternative targets holds significant potential for uncovering novel hits, but in the academic setting compound collections are rarely used, and shared, in this way. We present a short guide for collecting small molecules not being actively pursued in group projects (which we term “idlers”) to establish an open compound library. We describe how a diverse subset of this library was screened against a panel of pathogens, with the resulting data made publicly available. We hope to encourage other academic groups to develop and share their own libraries of idlers, thereby maximizing the utility of existing resources, enabling new insights, and catalyzing novel research directions through open science.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"23 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057142","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}
Pancreatic ductal adenocarcinoma (PDAC) remains challenging to diagnose in its early stages. Capitalizing on the established overexpression of plectin-1 in PDAC, we developed a novel plectin-1-targeted positron emission tomography (PET) radiotracer, [68Ga]Ga-NOTA-PTP, for precise PDAC imaging. The NOTA-PTP conjugate was synthesized, characterized, and efficiently radiolabeled with 68Ga, achieving high radiochemical purity (>99%). The radiotracer displayed a strong binding affinity for plectin-1 (IC50 = 12.8 nM) and exhibited time-dependent accumulation in PDAC cells. In murine PDAC xenografts, PET imaging demonstrated the rapid and specific tumor uptake of [68Ga]Ga-NOTA-PTP, enabling the visualization of peritoneal metastases. Targeting specificity was further verified by both the significant reduction in tumor uptake upon preadministration of the unlabeled compound and the positive correlation between tracer accumulation and plectin-1 expression levels. Collectively, this work introduces the first plectin-1-targeted PET probe for specific and sensitive detection of PDAC and metastatic lesions through efficient plectin-1 engagement.
{"title":"Radiosynthesis and Preclinical Evaluation of [68Ga]Ga-NOTA-PTP Profiling Plectin-1 Expression for Pancreatic Cancer Imaging.","authors":"Tingting Wang,Jingchao Li,Xiangping Chen,Xun Zhang,Dongsheng Zhang,Guangfa Wang,Jian Li,Yafei Zhang,Nian Liu,Xiao Chen,Xinhui Su","doi":"10.1021/acs.jmedchem.5c02777","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02777","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains challenging to diagnose in its early stages. Capitalizing on the established overexpression of plectin-1 in PDAC, we developed a novel plectin-1-targeted positron emission tomography (PET) radiotracer, [68Ga]Ga-NOTA-PTP, for precise PDAC imaging. The NOTA-PTP conjugate was synthesized, characterized, and efficiently radiolabeled with 68Ga, achieving high radiochemical purity (>99%). The radiotracer displayed a strong binding affinity for plectin-1 (IC50 = 12.8 nM) and exhibited time-dependent accumulation in PDAC cells. In murine PDAC xenografts, PET imaging demonstrated the rapid and specific tumor uptake of [68Ga]Ga-NOTA-PTP, enabling the visualization of peritoneal metastases. Targeting specificity was further verified by both the significant reduction in tumor uptake upon preadministration of the unlabeled compound and the positive correlation between tracer accumulation and plectin-1 expression levels. Collectively, this work introduces the first plectin-1-targeted PET probe for specific and sensitive detection of PDAC and metastatic lesions through efficient plectin-1 engagement.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"87 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056884","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}
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease with a high global incidence rate, intricately linked to metabolic disorders. It is characterized by steatosis, inflammation, and hepatocyte ballooning. STAT1 is a transcription factor involved in metabolic regulation and progression of inflammatory responses. In this study, we have identified STAT1 as a novel therapeutic target for NASH. Using our established STAT1 inhibitor screening platform, we identified the compound ZDZ-553, which is characterized by a chromone skeleton, demonstrates potent inhibitory activity against STAT1, and exhibits a favorable safety profile. In the NASH mouse model experiment, ZDZ-553 significantly ameliorated liver steatosis and inflammatory responses. These findings collectively suggest that ZDZ-553 could be a promising candidate for treatment of NASH, highlighting the therapeutic potential of targeting STAT1.
{"title":"Design, Synthesis, and Biological Evaluation of Chromone Derivatives as STAT1 Inhibitors for Treatment of Nonalcoholic Steatohepatitis","authors":"Zhipeng Zhang, Hongyan Lai, Shaofang Tian, Yingjie Song, Cunwuliji Na, Xiang Shi, Changhong He, Liuye Shi, Shengyun Wang, Fawad Ali, Fu Shu, Baoshun Zhang","doi":"10.1021/acs.jmedchem.5c02431","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02431","url":null,"abstract":"Nonalcoholic steatohepatitis (NASH) is a chronic liver disease with a high global incidence rate, intricately linked to metabolic disorders. It is characterized by steatosis, inflammation, and hepatocyte ballooning. STAT1 is a transcription factor involved in metabolic regulation and progression of inflammatory responses. In this study, we have identified STAT1 as a novel therapeutic target for NASH. Using our established STAT1 inhibitor screening platform, we identified the compound <b>ZDZ-553</b>, which is characterized by a chromone skeleton, demonstrates potent inhibitory activity against STAT1, and exhibits a favorable safety profile. In the NASH mouse model experiment, <b>ZDZ-553</b> significantly ameliorated liver steatosis and inflammatory responses. These findings collectively suggest that <b>ZDZ-553</b> could be a promising candidate for treatment of NASH, highlighting the therapeutic potential of targeting STAT1.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"28 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048697","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}
Seizure-related 6 homologue (SEZ6) is a highly expressed transmembrane protein that has emerged as a promising therapeutic target for small-cell lung cancer (SCLC). In this study, we developed a novel immuno-positron emission tomography probe ([64Cu]Cu-NOTA-GGB02-F9) based on the SEZ6-targeting antibody, GGB02-F9, for use in preclinical mouse models of SCLC. The diagnostic potential of [64Cu]Cu-NOTA-GGB02-F9 was evaluated in preclinical SCLC models with varying levels of SEZ6 expression. The H69 tumors exhibited a distinct accumulation of tracer uptake in the tumor xenograft mice, reaching a maximum uptake at 72 h postinjection, which was significantly higher than that in the H69 GGB02-F9-blocked and H460 groups (P < 0.01) at 24, 48, and 72 h postinjection. The uptake of the tumor tracer in mice was found to be associated with SEZ6 expression, as determined by immunohistochemical analysis. Our study demonstrated that [64Cu]Cu-NOTA-GGB02-F9 can noninvasively evaluate SEZ6 expression in preclinical SCLC mouse models.
{"title":"Novel ImmunoPET Probes [64Cu]Cu-NOTA-GGB02-F9 for Small-Cell Lung Cancer Derived from a SEZ6-Targeting Antibody","authors":"Guanyun Wang, Lingling Zheng, Xu Yang, Xiaoya Wang, Zi’ang Zhou, Ying Kan, Wei Wang, Jianhua Gong, Jigang Yang","doi":"10.1021/acs.jmedchem.5c02806","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02806","url":null,"abstract":"Seizure-related 6 homologue (SEZ6) is a highly expressed transmembrane protein that has emerged as a promising therapeutic target for small-cell lung cancer (SCLC). In this study, we developed a novel immuno-positron emission tomography probe ([<sup>64</sup>Cu]Cu-NOTA-GGB02-F9) based on the SEZ6-targeting antibody, GGB02-F9, for use in preclinical mouse models of SCLC. The diagnostic potential of [<sup>64</sup>Cu]Cu-NOTA-GGB02-F9 was evaluated in preclinical SCLC models with varying levels of SEZ6 expression. The H69 tumors exhibited a distinct accumulation of tracer uptake in the tumor xenograft mice, reaching a maximum uptake at 72 h postinjection, which was significantly higher than that in the H69 GGB02-F9-blocked and H460 groups (<i>P</i> < 0.01) at 24, 48, and 72 h postinjection. The uptake of the tumor tracer in mice was found to be associated with SEZ6 expression, as determined by immunohistochemical analysis. Our study demonstrated that [<sup>64</sup>Cu]Cu-NOTA-GGB02-F9 can noninvasively evaluate SEZ6 expression in preclinical SCLC mouse models.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"60 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048699","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}
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