Over the years, numerous ligand-based organotin(IV) Schiff base compounds have shown remarkable cytotoxicity and anticancer activities, but their clinical use is restricted by systemic toxicity, prompting the search for targeted therapies. Targeted delivery can be enhanced by exploiting the inherent characteristics of cancer cells such as glutamine addiction, which is essential to support cellular biosynthesis and cell growth to sustain aberrant proliferation. Our previous study revealed glutamine-conjugated organotin(IV) compounds have strong DNA/protein affinities, favorable in silico ADME profiles, and significant antiproliferative activity. In this study, these compounds demonstrated significant cytotoxicity against human colon carcinoma and adenocarcinoma cell lines via the induction of cell cycle arrest and apoptosis. In DMH/DSS-induced experimental colon carcinogenesis, these compounds reduced tumor burden and volume and inhibited cell proliferation and induced apoptosis, with minimal toxicity. Tissue distribution studies revealed selective accumulation in the colon. These findings support their potential as chemotherapeutic candidates for colon cancer.
{"title":"Evaluation of Anticancer Activity of Novel and Tumor-Targeted Glutamine-Conjugated Organotin(IV) Compounds in Colorectal Cancer─An In Vitro and In Vivo Study","authors":"Shagun Sharma, Varinder Kaur, Pratibha Duhan, Raghubir Singh, Navneet Agnihotri","doi":"10.1021/acs.jmedchem.4c01728","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01728","url":null,"abstract":"Over the years, numerous ligand-based organotin(IV) Schiff base compounds have shown remarkable cytotoxicity and anticancer activities, but their clinical use is restricted by systemic toxicity, prompting the search for targeted therapies. Targeted delivery can be enhanced by exploiting the inherent characteristics of cancer cells such as glutamine addiction, which is essential to support cellular biosynthesis and cell growth to sustain aberrant proliferation. Our previous study revealed glutamine-conjugated organotin(IV) compounds have strong DNA/protein affinities, favorable in silico ADME profiles, and significant antiproliferative activity. In this study, these compounds demonstrated significant cytotoxicity against human colon carcinoma and adenocarcinoma cell lines via the induction of cell cycle arrest and apoptosis. In DMH/DSS-induced experimental colon carcinogenesis, these compounds reduced tumor burden and volume and inhibited cell proliferation and induced apoptosis, with minimal toxicity. Tissue distribution studies revealed selective accumulation in the colon. These findings support their potential as chemotherapeutic candidates for colon cancer.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"74 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991018","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 : 2025-01-21DOI: 10.1021/acs.jmedchem.4c02634
Sai Yang, Xiaowen Gu, Lei Chen, Weixing Zhu
Synthetic lethality offers a robust strategy for discovering the next generation of precision medicine therapies tailored for molecularly defined patient populations. MAT2A inhibition is synthetically lethal in several cancers that exhibit a homozygous deletion of S-methyl-5′-thioadenosine phosphorylase (MTAP). Herein, we report the identification of novel MAT2A inhibitors featuring a spiral ring to circumvent the C–N atropisomeric chirality utilizing structure-based drug design. The Hit compound 9 exhibited high potency in enzymatic activity (IC50 = 7 nM) and in HCT-116 MTAP(−/−) cell potency (IC50 = 17 nM). Further optimization has led to the identification of two new lead compounds: a brain-penetrant compound, 29–1, and a potent but limited brain-penetrant compound, 39. Both of these lead compounds demonstrate increased plasma drug exposure and exhibit significant efficacy in xenograft models that are depleted of MTAP. We hope that identifying a brain-penetrant MAT2A inhibitor will create new opportunities to explore the potential therapeutic effects of S-adenosylmethionine modulation in the central nervous system.
{"title":"Discovery of Novel Spirocyclic MAT2A Inhibitors Demonstrating High In Vivo Efficacy in MTAP-Null Xenograft Models","authors":"Sai Yang, Xiaowen Gu, Lei Chen, Weixing Zhu","doi":"10.1021/acs.jmedchem.4c02634","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02634","url":null,"abstract":"Synthetic lethality offers a robust strategy for discovering the next generation of precision medicine therapies tailored for molecularly defined patient populations. MAT2A inhibition is synthetically lethal in several cancers that exhibit a homozygous deletion of <i>S</i>-methyl-5′-thioadenosine phosphorylase (MTAP). Herein, we report the identification of novel MAT2A inhibitors featuring a spiral ring to circumvent the C–N atropisomeric chirality utilizing structure-based drug design. The Hit compound <b>9</b> exhibited high potency in enzymatic activity (IC<sub>50</sub> = 7 nM) and in HCT-116 MTAP<sup>(−/−)</sup> cell potency (IC<sub>50</sub> = 17 nM). Further optimization has led to the identification of two new lead compounds: a brain-penetrant compound, <b>29–1</b>, and a potent but limited brain-penetrant compound, <b>39</b>. Both of these lead compounds demonstrate increased plasma drug exposure and exhibit significant efficacy in xenograft models that are depleted of MTAP. We hope that identifying a brain-penetrant MAT2A inhibitor will create new opportunities to explore the potential therapeutic effects of <i>S</i>-adenosylmethionine modulation in the central nervous system.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"71 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991020","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}
Since decades after temozolomide was approved, no effective drugs have been developed. Undoubtedly, blood–brain barrier (BBB) penetration is a severe issue that should be overcome in glioblastoma multiforme (GBM) drug development. In this research, we were inspired by linezolid through structural modification with several bioactive moieties to achieve the desired brain delivery. The results indicated that the histone deacetylase modification, referred to as compound 1, demonstrated promising cytotoxic effects in various brain tumor cell lines. Further comprehensive mechanism studies indicated that compound 1 induced acetylation, leading to DNA double-strand breaks, and induced the ubiquitination of RAD51, disrupting the DNA repair process. Furthermore, compound 1 also exhibited dramatic improvement in the orthotopic GBM mouse model, demonstrating its efficacy and satisfying BBB penetration. Therefore, the reported compound 1, provided with an independent therapeutic pathway, satisfying elongation in survival and tumor size reduction, and the ability to penetrate the BBB, was potent to achieve further development.
{"title":"Repurposing Linezolid in Conjunction with Histone Deacetylase Inhibitor Access in the Realm of Glioblastoma Therapies","authors":"I-Chung Chen, Hong-Yi Lin, Zheng-Yang Liu, Wei-Jie Cheng, Tzu-Yi Yeh, Wen-Bin Yang, Hoang Yen Tran, Mei-Jung Lai, Chung-Han Wang, Tzu-Yuan Kao, Chia-Yang Hung, Ya-Lin Huang, Ke-Chi Liou, Chien-Ming Hsieh, Tsung-I Hsu, Jing-Ping Liou","doi":"10.1021/acs.jmedchem.4c02086","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02086","url":null,"abstract":"Since decades after temozolomide was approved, no effective drugs have been developed. Undoubtedly, blood–brain barrier (BBB) penetration is a severe issue that should be overcome in glioblastoma multiforme (GBM) drug development. In this research, we were inspired by linezolid through structural modification with several bioactive moieties to achieve the desired brain delivery. The results indicated that the histone deacetylase modification, referred to as compound <b>1</b>, demonstrated promising cytotoxic effects in various brain tumor cell lines. Further comprehensive mechanism studies indicated that compound <b>1</b> induced acetylation, leading to DNA double-strand breaks, and induced the ubiquitination of RAD51, disrupting the DNA repair process. Furthermore, compound <b>1</b> also exhibited dramatic improvement in the orthotopic GBM mouse model, demonstrating its efficacy and satisfying BBB penetration. Therefore, the reported compound <b>1</b>, provided with an independent therapeutic pathway, satisfying elongation in survival and tumor size reduction, and the ability to penetrate the BBB, was potent to achieve further development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991019","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 : 2025-01-21DOI: 10.1021/acs.jmedchem.4c00691
Abdul Mannan Baig, Sandy Rosko, Beate Jaeger, Joachim Gerlach
In addition to the conventional symptoms reported for COVID-19, it is becoming increasingly clear that patients with long COVID are exhibiting new symptoms due to the emergence of autoantibodies against G-protein-coupled receptors, among which human muscarinic cholinergic receptors (CHRMs) have been prominently reported. With a chronic condition such as long COVID, additional symptoms caused by anti-CHRM autoantibodies (AAbs) have proven to be an added burden on these patients. The origins of these AAbs, their interactions with, and effects on the function of neural and non-neural cells within the nervous system have remained unknown. Furthermore, the specific symptom complex to which they contribute has not been clearly understood. In this context, we address these issues here and suggest methods to combat the autoantibodies that contribute to neurological symptoms in long COVID.
{"title":"Strategic Inhibition of CHRM Autoantibodies: Molecular Insights and Therapeutic Potentials in Long COVID","authors":"Abdul Mannan Baig, Sandy Rosko, Beate Jaeger, Joachim Gerlach","doi":"10.1021/acs.jmedchem.4c00691","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c00691","url":null,"abstract":"In addition to the conventional symptoms reported for COVID-19, it is becoming increasingly clear that patients with long COVID are exhibiting new symptoms due to the emergence of autoantibodies against G-protein-coupled receptors, among which human muscarinic cholinergic receptors (CHRMs) have been prominently reported. With a chronic condition such as long COVID, additional symptoms caused by anti-CHRM autoantibodies (AAbs) have proven to be an added burden on these patients. The origins of these AAbs, their interactions with, and effects on the function of neural and non-neural cells within the nervous system have remained unknown. Furthermore, the specific symptom complex to which they contribute has not been clearly understood. In this context, we address these issues here and suggest methods to combat the autoantibodies that contribute to neurological symptoms in long COVID.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"46 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991017","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 : 2025-01-20DOI: 10.1021/acs.jmedchem.4c02399
Claudio Papotto, Clare Stokes, Carlo Matera, Sara M. Herz, Ka Chiang, Rebecca Ferrisi, Marco De Amici, M. Imad Damaj, Roger L. Papke, Clelia Dallanoce
In the pressing quest of novel treatments for chronic pain, α7 nAChR silent agonists show efficacy as anti-inflammatory modulators and represent a promising strategy. Recent findings reveal that a sulfonium ion can replace the quaternary ammonium nitrogen as an alternative pharmacophore for nAChR silent activation. This study reports the design, synthesis, and electrophysiological evaluation of a new series of sulfonium-based derivatives inspired by the archetypal silent agonist NS6740. Our findings identify NSS-9 as a novel sulfonium α7 silent agonist that effectively alleviates inflammatory pain in a mouse model, highlighting it as a lead compound for further optimization. These results provide insights into the potential of the sulfonium group as a chemotype interacting with the α7 binding site, making it a valuable scaffold for novel α7 silent agonists. Additionally, sulfonium compounds were tested on α9 nAChR, also involved in the cholinergic anti-inflammatory system, identifying one partial agonist and two antagonists.
{"title":"Sulfonium Moieties as Ammonium Bioisosteres: Novel Ligands for the Alpha7 Nicotinic Acetylcholine Receptor","authors":"Claudio Papotto, Clare Stokes, Carlo Matera, Sara M. Herz, Ka Chiang, Rebecca Ferrisi, Marco De Amici, M. Imad Damaj, Roger L. Papke, Clelia Dallanoce","doi":"10.1021/acs.jmedchem.4c02399","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02399","url":null,"abstract":"In the pressing quest of novel treatments for chronic pain, α7 nAChR silent agonists show efficacy as anti-inflammatory modulators and represent a promising strategy. Recent findings reveal that a sulfonium ion can replace the quaternary ammonium nitrogen as an alternative pharmacophore for nAChR silent activation. This study reports the design, synthesis, and electrophysiological evaluation of a new series of sulfonium-based derivatives inspired by the archetypal silent agonist NS6740. Our findings identify <b>NSS-9</b> as a novel sulfonium α7 silent agonist that effectively alleviates inflammatory pain in a mouse model, highlighting it as a lead compound for further optimization. These results provide insights into the potential of the sulfonium group as a chemotype interacting with the α7 binding site, making it a valuable scaffold for novel α7 silent agonists. Additionally, sulfonium compounds were tested on α9 nAChR, also involved in the cholinergic anti-inflammatory system, identifying one partial agonist and two antagonists.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"57 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989692","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 : 2025-01-20DOI: 10.1021/acs.jmedchem.4c01556
Nicholas A. Weirath, Jonathan W. P. Zajac, Haley M. Donow, Travis M. Lavoi, Clemencia Pinilla, Radleigh G. Santos, Ritu Prajapati, Robert Speth, Mark D. Ericson, Sapna Sarupria, Marcello A. Giulianotti, Carrie Haskell-Luevano
The melanocortin receptors are a class of centrally and peripherally expressed G protein-coupled receptors, of which the MC3R and MC4R subtypes are implicated in the regulation of appetite and energy homeostasis and can serve as potential therapeutic targets for disorders such as obesity and cachexia. An unbiased high-throughput mixture-based library screen was implemented to identify novel ligands with an emphasis on the identification of nanomolar-potent agonists of the mouse melanocortin-3 receptor. This screen yielded the discovery of an N-branched tricyclic guanidine scaffold (TPI2408) that contained three nanomolar potent mMC3R agonists and additional compounds that possessed antagonism for the mMC4R. The antagonist character of this scaffold library at the mMC4R was confirmed by a follow-up positional scanning antagonist screen. Additionally, molecular dynamics simulations herein provide mechanistic insight into the polypharmacological characteristics of melanocortin receptors. The disclosed materials have the potential to serve as important tools and SAR scaffolds in the study of melanocortin receptor function.
{"title":"N-Branched Tricyclic Guanidines as Novel Melanocortin-3 Receptor Agonists and Melanocortin-4 Receptor Antagonists","authors":"Nicholas A. Weirath, Jonathan W. P. Zajac, Haley M. Donow, Travis M. Lavoi, Clemencia Pinilla, Radleigh G. Santos, Ritu Prajapati, Robert Speth, Mark D. Ericson, Sapna Sarupria, Marcello A. Giulianotti, Carrie Haskell-Luevano","doi":"10.1021/acs.jmedchem.4c01556","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01556","url":null,"abstract":"The melanocortin receptors are a class of centrally and peripherally expressed G protein-coupled receptors, of which the MC3R and MC4R subtypes are implicated in the regulation of appetite and energy homeostasis and can serve as potential therapeutic targets for disorders such as obesity and cachexia. An unbiased high-throughput mixture-based library screen was implemented to identify novel ligands with an emphasis on the identification of nanomolar-potent agonists of the mouse melanocortin-3 receptor. This screen yielded the discovery of an N-branched tricyclic guanidine scaffold (TPI2408) that contained three nanomolar potent mMC3R agonists and additional compounds that possessed antagonism for the mMC4R. The antagonist character of this scaffold library at the mMC4R was confirmed by a follow-up positional scanning antagonist screen. Additionally, molecular dynamics simulations herein provide mechanistic insight into the polypharmacological characteristics of melanocortin receptors. The disclosed materials have the potential to serve as important tools and SAR scaffolds in the study of melanocortin receptor function.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991021","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}
Fluorescence molecular imaging aims to enhance clarity in the region of interest, particularly in the near-infrared IIb window (NIR-IIb, 1500–1700 nm). To achieve this, we developed a novel small-molecule dye, named DA-5, based on classic cyanine dyes (heptamethine or pentamethine is essential for wavelengths beyond 1000 nm). By reducing excessive polymethine to a single methine and disrupting symmetry to form an asymmetric donor-π-acceptor (D-π-A) architecture, we enhanced the donor’s electron-donating capability, yielding emission at 1088 nm. DA-5 exhibits superior properties, including excellent chemo- and photostability, resistance against solvatochromism-caused quenching, and antiaggregation in aqueous solution. With a large Stokes shift (241 nm) and high brightness (321 M–1 cm–1), DA-5 enables high-performance imaging of the lymphatic system, intestinal vessels, whole-body angiography, and cerebral and hindlimb microvasculature in NIR-IIb. This molecular design strategy offers a promising platform for advancing in vivo biophotonics.
{"title":"Less Is More: Donor Engineering of a Stable Molecular Dye for Bioimaging in the NIR-IIb Window","authors":"Tianbao Wang, Yufei Qin, Jin-yu Wang, Yihan Xu, Jiaming Guo, Yiling Zhu, Huiyan Zhang, Yujie Qin, Zhong-Quan Qi, Hualong Fu, Ya-jun Liu, Mengchao Cui, Kaixiang Zhou","doi":"10.1021/acs.jmedchem.4c02866","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02866","url":null,"abstract":"Fluorescence molecular imaging aims to enhance clarity in the region of interest, particularly in the near-infrared IIb window (NIR-IIb, 1500–1700 nm). To achieve this, we developed a novel small-molecule dye, named <b>DA-5</b>, based on classic cyanine dyes (heptamethine or pentamethine is essential for wavelengths beyond 1000 nm). By reducing excessive polymethine to a single methine and disrupting symmetry to form an asymmetric donor-π-acceptor (D-π-A) architecture, we enhanced the donor’s electron-donating capability, yielding emission at 1088 nm. <b>DA-5</b> exhibits superior properties, including excellent chemo- and photostability, resistance against solvatochromism-caused quenching, and antiaggregation in aqueous solution. With a large Stokes shift (241 nm) and high brightness (321 M<sup>–1</sup> cm<sup>–1</sup>), <b>DA-5</b> enables high-performance imaging of the lymphatic system, intestinal vessels, whole-body angiography, and cerebral and hindlimb microvasculature in NIR-IIb. This molecular design strategy offers a promising platform for advancing in vivo biophotonics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"28 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989693","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 : 2025-01-18DOI: 10.1021/acs.jmedchem.4c02231
Ting Zhang, Baoyin Yang, Tao Jiang, Xiangyu Kong, Xinyao Huo, Yan Ma, Kehao Yang, Mengchun Liu, Yumiao Liu, Zikuo Yao, Hao Yu, Huining Liu, Kai Zhang, Yifan Liu
For cancer treatment, collaborative strategies have been the mainstream for overcoming the restrictions resulting from monotherapy. Combining chemotherapy with photodynamic therapy (PDT) has been shown to increase the antitumor effect and reduce side impacts. This study reports a hypoxia-activated prodrug BOD-Azo-single with a PDT agent and aniline mustard connected by the azo bond. With light illumination, BOD-Azo-single exhibited some PDT. Under hypoxic conditions, the azo bond cleaved and released BOD-3-single of higher phototoxicity and aniline mustard of chemotoxicity. In vivo therapeutic experiments showed that BOD-Azo-single with light significantly reduced A375 tumor proliferation with 92% TGI value. Overall, in this study, PDT was employed to address the adverse systemic toxicity of chemotherapy and the released chemotoxicity made up for the inefficiency of PDT in the hypoxic tumor microenvironment, introducing a new strategy for developing combined therapeutic agents to be advantageous to each other. Under a hypoxic tumor environment, BOD-3-single and aniline mustard exerted a strong synergistic effect (CI = 0.25), indicating that BOD-Azo-single is a real bimodal chemo-photodynamic therapeutic agent.
{"title":"A Hypoxia-Activated BODIPY-Azo Anticancer Prodrug for Bimodal Chemo-Photodynamic Therapy","authors":"Ting Zhang, Baoyin Yang, Tao Jiang, Xiangyu Kong, Xinyao Huo, Yan Ma, Kehao Yang, Mengchun Liu, Yumiao Liu, Zikuo Yao, Hao Yu, Huining Liu, Kai Zhang, Yifan Liu","doi":"10.1021/acs.jmedchem.4c02231","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02231","url":null,"abstract":"For cancer treatment, collaborative strategies have been the mainstream for overcoming the restrictions resulting from monotherapy. Combining chemotherapy with photodynamic therapy (PDT) has been shown to increase the antitumor effect and reduce side impacts. This study reports a hypoxia-activated prodrug BOD-Azo-single with a PDT agent and aniline mustard connected by the azo bond. With light illumination, BOD-Azo-single exhibited some PDT. Under hypoxic conditions, the azo bond cleaved and released BOD-3-single of higher phototoxicity and aniline mustard of chemotoxicity. <i>In vivo</i> therapeutic experiments showed that BOD-Azo-single with light significantly reduced A375 tumor proliferation with 92% TGI value. Overall, in this study, PDT was employed to address the adverse systemic toxicity of chemotherapy and the released chemotoxicity made up for the inefficiency of PDT in the hypoxic tumor microenvironment, introducing a new strategy for developing combined therapeutic agents to be advantageous to each other. Under a hypoxic tumor environment, BOD-3-single and aniline mustard exerted a strong synergistic effect (CI = 0.25), indicating that BOD-Azo-single is a real bimodal chemo-photodynamic therapeutic agent.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"24 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989536","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 : 2025-01-17DOI: 10.1021/acs.jmedchem.4c02989
Yimin Chen, Wanjia Liu, Ben Li, Xi Gao, Kaixiang Zhou, Mingxin Zhang, Guangjie Yang, Mengchao Cui
Precise surgical resection of prostate cancer (PCa) is a significant clinical challenge due to the impact of positive surgical margins on postoperative outcomes. Fluorescence-guided surgery (FGS) enables real-time tumor visualization using fluorescent probes. In this study, we synthesized and evaluated an indocyanine green (ICG)-based PSMA-targeted near-infrared probe, ICG-PSMA-D5, for intraoperative imaging of PCa lesions. Spectroscopic analysis revealed that ICG-PSMA-D5 retained the optical properties of ICG while improving solubility in PBS due to additional carboxyl groups. In vitro assays demonstrated high binding affinity (Ki = 0.39 nM) and minimal cytotoxicity. In vivo studies in tumor-bearing mice showed strong tumor targeting, extended retention at tumor site, and favorable biodistribution, with significant tumor-to-background ratios. The first-in-human study in a patient with localized PCa indicated the probe’s potential for real-time, radiation-free surgical guidance. Overall, ICG-PSMA-D5 displayed excellent performance in tumor detection and margin delineation, making it a promising candidate for intraoperative FGS in PCa.
{"title":"Synthesis, Preclinical Evaluation, and First-in-Human Assessment of ICG-PSMA-D5: A PSMA-Targeted Probe for Fluorescence-Guided Surgery of Prostate Cancer","authors":"Yimin Chen, Wanjia Liu, Ben Li, Xi Gao, Kaixiang Zhou, Mingxin Zhang, Guangjie Yang, Mengchao Cui","doi":"10.1021/acs.jmedchem.4c02989","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02989","url":null,"abstract":"Precise surgical resection of prostate cancer (PCa) is a significant clinical challenge due to the impact of positive surgical margins on postoperative outcomes. Fluorescence-guided surgery (FGS) enables real-time tumor visualization using fluorescent probes. In this study, we synthesized and evaluated an indocyanine green (ICG)-based PSMA-targeted near-infrared probe, <b>ICG-PSMA-D5</b>, for intraoperative imaging of PCa lesions. Spectroscopic analysis revealed that <b>ICG-PSMA-D5</b> retained the optical properties of <b>ICG</b> while improving solubility in PBS due to additional carboxyl groups. <i>In vitro</i> assays demonstrated high binding affinity (<i>K</i><sub>i</sub> = 0.39 nM) and minimal cytotoxicity. <i>In vivo</i> studies in tumor-bearing mice showed strong tumor targeting, extended retention at tumor site, and favorable biodistribution, with significant tumor-to-background ratios. The first-in-human study in a patient with localized PCa indicated the probe’s potential for real-time, radiation-free surgical guidance. Overall, <b>ICG-PSMA-D5</b> displayed excellent performance in tumor detection and margin delineation, making it a promising candidate for intraoperative FGS in PCa.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"35 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989543","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 : 2025-01-17DOI: 10.1021/acs.jmedchem.4c02377
Benjamin C. Milgram, Deanna R. Borrelli, Natasja Brooijmans, Jack A. Henderson, Brendan J. Hilbert, Michael R. Huff, Takahiro Ito, Erica L. Jackson, Philip Jonsson, Brendon Ladd, Erin L. O’Hearn, Raymond A. Pagliarini, Simon A. Roberts, Sébastien Ronseaux, Darrin D. Stuart, Weixue Wang, Angel Guzman-Perez
After L858R and ex19del epidermal growth factor receptor (EGFR) mutations, ex20ins mutations are the third most common class of driver-mutations in non-small cell lung cancer (NSCLC). Unfortunately, first-, second-, and third-generation EGFR tyrosine kinase inhibitors (TKIs) are generally ineffective for ex20ins patients due to insufficient mutant activity and selectivity over wild-type EGFR, leading to dose-limiting toxicities. While significant advances in recent years have been made toward identifying potent EGFR ex20ins mutant inhibitors, mutant vs wild-type EGFR selectivity remains a significant challenge. STX-721 (53) is a potent, irreversible inhibitor of the majority of EGFR/HER2 ex20ins mutants and demonstrates excellent mutant vs wild-type selectivity both in vitro and in vivo. STX-721 is currently in phase 1/2 clinical trials for EGFR/HER2 ex20ins-driven NSCLC.
{"title":"Discovery of STX-721, a Covalent, Potent, and Highly Mutant-Selective EGFR/HER2 Exon20 Insertion Inhibitor for the Treatment of Non-Small Cell Lung Cancer","authors":"Benjamin C. Milgram, Deanna R. Borrelli, Natasja Brooijmans, Jack A. Henderson, Brendan J. Hilbert, Michael R. Huff, Takahiro Ito, Erica L. Jackson, Philip Jonsson, Brendon Ladd, Erin L. O’Hearn, Raymond A. Pagliarini, Simon A. Roberts, Sébastien Ronseaux, Darrin D. Stuart, Weixue Wang, Angel Guzman-Perez","doi":"10.1021/acs.jmedchem.4c02377","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02377","url":null,"abstract":"After L858R and ex19del epidermal growth factor receptor (EGFR) mutations, ex20ins mutations are the third most common class of driver-mutations in non-small cell lung cancer (NSCLC). Unfortunately, first-, second-, and third-generation EGFR tyrosine kinase inhibitors (TKIs) are generally ineffective for ex20ins patients due to insufficient mutant activity and selectivity over wild-type EGFR, leading to dose-limiting toxicities. While significant advances in recent years have been made toward identifying potent EGFR ex20ins mutant inhibitors, mutant vs wild-type EGFR selectivity remains a significant challenge. STX-721 (<b>53</b>) is a potent, irreversible inhibitor of the majority of EGFR/HER2 ex20ins mutants and demonstrates excellent mutant vs wild-type selectivity both in vitro and in vivo. STX-721 is currently in phase 1/2 clinical trials for EGFR/HER2 ex20ins-driven NSCLC.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"56 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989541","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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