Pub Date : 2025-01-24DOI: 10.1021/acs.jmedchem.5c00076
Congbao Kang, Weijun Xu
The discovery of molecular glues has made significant strides, unlocking new avenues for targeted protein degradation as a therapeutic strategy, thereby expanding the scope of drug discovery into territories previously considered undruggable. Pioneering molecules like thalidomide and its derivatives have paved the way for the development of small molecules that can induce specific protein degradation by hijacking the cellular ubiquitin–proteasome system. Recent advancements have focused on expanding the range of E3 ligases and target proteins that can be modulated by molecular glues. Structural elucidation of E3 ligase in complex with molecular glue and the target of interest, combined with computational modeling, facilitates the understanding of the underlying mechanisms of how molecular glues induce targeted degradation. By leveraging these tools, the next generation of molecular glues are expected to offer unprecedented opportunities for combating a wide range of diseases, including cancer, autoimmune disorders, and neurodegenerative conditions.
{"title":"Leveraging Structural and Computational Biology for Molecular Glue Discovery","authors":"Congbao Kang, Weijun Xu","doi":"10.1021/acs.jmedchem.5c00076","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00076","url":null,"abstract":"The discovery of molecular glues has made significant strides, unlocking new avenues for targeted protein degradation as a therapeutic strategy, thereby expanding the scope of drug discovery into territories previously considered undruggable. Pioneering molecules like thalidomide and its derivatives have paved the way for the development of small molecules that can induce specific protein degradation by hijacking the cellular ubiquitin–proteasome system. Recent advancements have focused on expanding the range of E3 ligases and target proteins that can be modulated by molecular glues. Structural elucidation of E3 ligase in complex with molecular glue and the target of interest, combined with computational modeling, facilitates the understanding of the underlying mechanisms of how molecular glues induce targeted degradation. By leveraging these tools, the next generation of molecular glues are expected to offer unprecedented opportunities for combating a wide range of diseases, including cancer, autoimmune disorders, and neurodegenerative conditions.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"109 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030752","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 : 2025-01-24DOI: 10.1021/acs.jmedchem.4c01691
Margot Boujut, Margaux Héritier, Aurélie Gouiller, Camille Süess, Alessandro Scapozza, Thibaut De Smedt, Maxime Guibert, Sébastien Tardy, Hesham M. Ismail, David Pejoski, Leonardo Scapozza
Inhibition of the adenosine 2A receptor (A2AR) is recognized as a promising immunotherapeutic strategy but is challenged by the ubiquity of A2AR function in the immune system. To develop a safe yet efficacious immunotherapy, the discovery of a novel negative allosteric modulator (NAM) was preferred. Leveraging an in-house, sensitive, high-throughput screening cellular assay, novel A2AR NAM scaffolds were identified, followed by an extensive structure–activity relationship (SAR) study, leading to the discovery of potent 2-amino-3,5-dicyanopyridine derivatives. The allosteric mode of action of active compounds was confirmed by progressive fold-shift assay, nonlinearity of the Schild plot analysis, biophysical measurements, and retained satisfactory potencies in high-adenosine concentrations. Further correlation of A2AR engagement and downstream signaling was done in a human blood translational assay, clearly showcasing the potential of A2AR allosteric modulation as a novel approach for efficient and safer cancer immunotherapies.
{"title":"Discovery of the First Efficacious Adenosine 2A Receptor Negative Allosteric Modulators for High Adenosine Cancer Immunotherapies","authors":"Margot Boujut, Margaux Héritier, Aurélie Gouiller, Camille Süess, Alessandro Scapozza, Thibaut De Smedt, Maxime Guibert, Sébastien Tardy, Hesham M. Ismail, David Pejoski, Leonardo Scapozza","doi":"10.1021/acs.jmedchem.4c01691","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01691","url":null,"abstract":"Inhibition of the adenosine 2A receptor (A<sub>2A</sub>R) is recognized as a promising immunotherapeutic strategy but is challenged by the ubiquity of A<sub>2A</sub>R function in the immune system. To develop a safe yet efficacious immunotherapy, the discovery of a novel negative allosteric modulator (NAM) was preferred. Leveraging an in-house, sensitive, high-throughput screening cellular assay, novel A<sub>2A</sub>R NAM scaffolds were identified, followed by an extensive structure–activity relationship (SAR) study, leading to the discovery of potent 2-amino-3,5-dicyanopyridine derivatives. The allosteric mode of action of active compounds was confirmed by progressive fold-shift assay, nonlinearity of the Schild plot analysis, biophysical measurements, and retained satisfactory potencies in high-adenosine concentrations. Further correlation of A<sub>2A</sub>R engagement and downstream signaling was done in a human blood translational assay, clearly showcasing the potential of A<sub>2A</sub>R allosteric modulation as a novel approach for efficient and safer cancer immunotherapies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"29 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030717","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}
Based on our previous work, a series of imidazole-based small molecules were designed and synthesized as HDAC3 inhibitors. Among them, compound SC26 showed selective HDAC3 inhibition activity with an IC50 of 53 nM (SI = 75 for HDAC3 over HDAC1). Further studies revealed that SC26 could dose-dependently induce the expression of PD-L1 in MC38 cells by activating the PD-L1 transcription. SC26 also showed high in vivo antitumor efficacy in a colorectal cancer model (50 mg/kg po, TGI = 63%). Importantly, the combination of SC26 with the PD-L1 inhibitor NP19 activated the immune system in tumor-bearing mice, enhancing the antitumor immune response (TGI = 80%, 50 + 50 mg/kg, p.o.). Collectively, we report for the first time that an HDAC3 inhibitor could upregulate PD-L1 expression in vitro and in vivo, specifically in MC38 cells and MC38-bearing tumors, and SC26 represents a novel epigenetic immunomodulator with potential applications in tumor immunotherapy.
{"title":"Discovery of Novel Hydrazide-Based HDAC3 Inhibitors as Epigenetic Immunomodulators for Cancer Immunotherapy","authors":"Zhiqiang Sun, Jinmei Cheng, Chenglong Xu, Xuewen Zhang, Qinru Zang, Xixiang Yang, Yueyu He, Aiqi Su, Xiaopeng Peng, Jianjun Chen","doi":"10.1021/acs.jmedchem.4c02296","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02296","url":null,"abstract":"Based on our previous work, a series of imidazole-based small molecules were designed and synthesized as HDAC3 inhibitors. Among them, compound <b>SC26</b> showed selective HDAC3 inhibition activity with an IC<sub>50</sub> of 53 nM (SI = 75 for HDAC3 over HDAC1). Further studies revealed that <b>SC26</b> could dose-dependently induce the expression of PD-L1 in MC38 cells by activating the PD-L1 transcription. <b>SC26</b> also showed high in vivo antitumor efficacy in a colorectal cancer model (50 mg/kg po, TGI = 63%). Importantly, the combination of <b>SC26</b> with the PD-L1 inhibitor <b>NP19</b> activated the immune system in tumor-bearing mice, enhancing the antitumor immune response (TGI = 80%, 50 + 50 mg/kg, p.o.). Collectively, we report for the first time that an HDAC3 inhibitor could upregulate PD-L1 expression in vitro and in vivo, specifically in MC38 cells and MC38-bearing tumors, and <b>SC26</b> represents a novel epigenetic immunomodulator with potential applications in tumor immunotherapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"34 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026948","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 : 2025-01-23DOI: 10.1021/acs.jmedchem.4c02649
Jianing Liao, Jinbiao Liao, Ying Wang, Xinyue Wang, Xin Chai, Huating Wang, Lei Xu, Luhu Shan, Xiaohong Xu, Weitao Fu, Peichen Pan, Tingjun Hou, Rong Sheng, Dan Li
The ligand-binding pocket of the androgen receptor (AR) is the targeting site of all clinically used AR antagonists. However, various drug-resistant mutations emerged in the pocket. We previously reported a new targeting site at the dimer interface of AR (dimer interface pocket) and identified a novel antagonist M17-B15 that failed in oral administration. In this study, the head part of M17-B15 was substituted with divergent structures. Potent antagonist Z10 with benzo[b]oxepine was first identified. Subsequent structural optimization on the 2-oxopropyl moiety of Z10 generated the more powerful Y5 (IC50 = 0.04 μM). Out of the ordinary, Y5 demonstrated dual mechanisms of action, antagonized AR by disrupting AR dimerization, and induced AR degradation via the ubiquitin-proteasome pathway. Furthermore, Y5 exhibited excellent activity against variant drug-resistant AR mutants comparable to recently approved darolutamide. Furthermore, Y5 effectively suppressed the tumor growth of the LNCaP xenograft via oral administration, providing a potential novel therapeutic for drug-resistant prostate cancer.
{"title":"Discovery of N-(1,2,4-Thiadiazol-5-yl)benzo[b]oxepine-4-carboxamide Derivatives as Novel Antiresistance Androgen Receptor Antagonists","authors":"Jianing Liao, Jinbiao Liao, Ying Wang, Xinyue Wang, Xin Chai, Huating Wang, Lei Xu, Luhu Shan, Xiaohong Xu, Weitao Fu, Peichen Pan, Tingjun Hou, Rong Sheng, Dan Li","doi":"10.1021/acs.jmedchem.4c02649","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02649","url":null,"abstract":"The ligand-binding pocket of the androgen receptor (AR) is the targeting site of all clinically used AR antagonists. However, various drug-resistant mutations emerged in the pocket. We previously reported a new targeting site at the dimer interface of AR (dimer interface pocket) and identified a novel antagonist M17-B15 that failed in oral administration. In this study, the head part of M17-B15 was substituted with divergent structures. Potent antagonist <b>Z10</b> with benzo[<i>b</i>]oxepine was first identified. Subsequent structural optimization on the 2-oxopropyl moiety of <b>Z10</b> generated the more powerful <b>Y5</b> (IC<sub>50</sub> = 0.04 μM). Out of the ordinary, <b>Y5</b> demonstrated dual mechanisms of action, antagonized AR by disrupting AR dimerization, and induced AR degradation via the ubiquitin-proteasome pathway. Furthermore, <b>Y5</b> exhibited excellent activity against variant drug-resistant AR mutants comparable to recently approved darolutamide. Furthermore, <b>Y5</b> effectively suppressed the tumor growth of the LNCaP xenograft via oral administration, providing a potential novel therapeutic for drug-resistant prostate cancer.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"34 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026951","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 : 2025-01-23Epub Date: 2024-11-04DOI: 10.1021/acs.jmedchem.4c02010
Suzanne Ackloo, Fengling Li, Magda Szewczyk, Almagul Seitova, Peter Loppnau, Hong Zeng, Jin Xu, Shabbir Ahmad, Yelena A Arnautova, A J Baghaie, Serap Beldar, Albina Bolotokova, Paolo A Centrella, Irene Chau, Matthew A Clark, John W Cuozzo, Saba Dehghani-Tafti, Jeremy S Disch, Aiping Dong, Antoine Dumas, Jianwen A Feng, Pegah Ghiabi, Elisa Gibson, Justin Gilmer, Brian Goldman, Stuart R Green, Marie-Aude Guié, John P Guilinger, Nathan Harms, Oleksandra Herasymenko, Scott Houliston, Ashley Hutchinson, Steven Kearnes, Anthony D Keefe, Serah W Kimani, Trevor Kramer, Maria Kutera, Haejin A Kwak, Cristina Lento, Yanjun Li, Jenny Liu, Joachim Loup, Raquel A C Machado, Christopher J Mulhern, Sumera Perveen, Germanna L Righetto, Patrick Riley, Suman Shrestha, Eric A Sigel, Madhushika Silva, Michael D Sintchak, Belinda L Slakman, Rhys D Taylor, James Thompson, Wen Torng, Carl Underkoffler, Moritz von Rechenberg, Ryan T Walsh, Ian Watson, Derek J Wilson, Esther Wolf, Manisha Yadav, Aliakbar K Yazdi, Junyi Zhang, Ying Zhang, Vijayaratnam Santhakumar, Aled M Edwards, Dalia Barsyte-Lovejoy, Matthieu Schapira, Peter J Brown, Levon Halabelian, Cheryl H Arrowsmith
Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays. A pilot hit-finding campaign using DNA-encoded chemical library selection followed by machine learning (DEL-ML) to predict ligands from virtual libraries yielded first-in-class, drug-like ligands for 7 of the 16 WDR domains screened, thus demonstrating the broader ligandability of WDRs. This study establishes a template for evaluation of protein family wide ligandability and provides an extensive resource of WDR protein biochemical and chemical tools, knowledge, and protocols to discover potential therapeutics for this highly disease-relevant, but underexplored target class.
{"title":"A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins.","authors":"Suzanne Ackloo, Fengling Li, Magda Szewczyk, Almagul Seitova, Peter Loppnau, Hong Zeng, Jin Xu, Shabbir Ahmad, Yelena A Arnautova, A J Baghaie, Serap Beldar, Albina Bolotokova, Paolo A Centrella, Irene Chau, Matthew A Clark, John W Cuozzo, Saba Dehghani-Tafti, Jeremy S Disch, Aiping Dong, Antoine Dumas, Jianwen A Feng, Pegah Ghiabi, Elisa Gibson, Justin Gilmer, Brian Goldman, Stuart R Green, Marie-Aude Guié, John P Guilinger, Nathan Harms, Oleksandra Herasymenko, Scott Houliston, Ashley Hutchinson, Steven Kearnes, Anthony D Keefe, Serah W Kimani, Trevor Kramer, Maria Kutera, Haejin A Kwak, Cristina Lento, Yanjun Li, Jenny Liu, Joachim Loup, Raquel A C Machado, Christopher J Mulhern, Sumera Perveen, Germanna L Righetto, Patrick Riley, Suman Shrestha, Eric A Sigel, Madhushika Silva, Michael D Sintchak, Belinda L Slakman, Rhys D Taylor, James Thompson, Wen Torng, Carl Underkoffler, Moritz von Rechenberg, Ryan T Walsh, Ian Watson, Derek J Wilson, Esther Wolf, Manisha Yadav, Aliakbar K Yazdi, Junyi Zhang, Ying Zhang, Vijayaratnam Santhakumar, Aled M Edwards, Dalia Barsyte-Lovejoy, Matthieu Schapira, Peter J Brown, Levon Halabelian, Cheryl H Arrowsmith","doi":"10.1021/acs.jmedchem.4c02010","DOIUrl":"10.1021/acs.jmedchem.4c02010","url":null,"abstract":"<p><p>Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays. A pilot hit-finding campaign using DNA-encoded chemical library selection followed by machine learning (DEL-ML) to predict ligands from virtual libraries yielded first-in-class, drug-like ligands for 7 of the 16 WDR domains screened, thus demonstrating the broader ligandability of WDRs. This study establishes a template for evaluation of protein family wide ligandability and provides an extensive resource of WDR protein biochemical and chemical tools, knowledge, and protocols to discover potential therapeutics for this highly disease-relevant, but underexplored target class.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"1092-1112"},"PeriodicalIF":6.8,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566387","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}
Pub Date : 2025-01-23DOI: 10.1021/acs.jmedchem.4c02646
Chae Bin Lee, Ivan Šnajdr, Lukáš Tenora, Jesse Alt, Sadakatali Gori, Marcela Krečmerová, R. Michael Maragakis, James Paule, Sandhya Tiwari, Jitesh Iyer, Rashmi Talwar, Luis Garza, Pavel Majer, Barbara S. Slusher, Rana Rais
Itaconate, an endogenous immunomodulator from the tricarboxylic acid (TCA) cycle, shows therapeutic effects in various disease models, but is highly polar with poor cellular permeability. We previously reported a novel, topical itaconate derivative, SCD-153, for the treatment of alopecia areata. Here, we present the discovery of orally available itaconate derivatives for systemic and skin disorders. Four sets of prodrugs were synthesized using pivaloyloxymethyl (POM), isopropyloxycarbonyloxymethyl (POC), (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL), and 3-(hexadecyloxy)propyl (HDP) pro-moieties pairing with itaconic acid (IA), 1-methyl itaconate (1-MI), and 4-methyl itaconate (4-MI). Among these, POC-based prodrugs (P2, P9, P13) showed favorable stability, permeability, and pharmacokinetics. Notably, P2 and P13 significantly inhibited Poly(I:C)/IFNγ-induced inflammatory cytokines in human epidermal keratinocytes. Oral studies demonstrated favorable pharmacokinetics releasing micromolar concentrations of IA or 4-MI from P2 and P13, respectively. These findings highlight the potential of prodrug strategies to enhance itaconate’s cellular permeability and oral bioavailability, paving the way for clinical translation.
{"title":"Discovery of Orally Available Prodrugs of Itaconate and Derivatives","authors":"Chae Bin Lee, Ivan Šnajdr, Lukáš Tenora, Jesse Alt, Sadakatali Gori, Marcela Krečmerová, R. Michael Maragakis, James Paule, Sandhya Tiwari, Jitesh Iyer, Rashmi Talwar, Luis Garza, Pavel Majer, Barbara S. Slusher, Rana Rais","doi":"10.1021/acs.jmedchem.4c02646","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02646","url":null,"abstract":"Itaconate, an endogenous immunomodulator from the tricarboxylic acid (TCA) cycle, shows therapeutic effects in various disease models, but is highly polar with poor cellular permeability. We previously reported a novel, topical itaconate derivative, SCD-153, for the treatment of alopecia areata. Here, we present the discovery of orally available itaconate derivatives for systemic and skin disorders. Four sets of prodrugs were synthesized using pivaloyloxymethyl (POM), isopropyloxycarbonyloxymethyl (POC), (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL), and 3-(hexadecyloxy)propyl (HDP) pro-moieties pairing with itaconic acid (IA), 1-methyl itaconate (1-MI), and 4-methyl itaconate (4-MI). Among these, POC-based prodrugs (<b>P2</b>, <b>P9</b>, <b>P13</b>) showed favorable stability, permeability, and pharmacokinetics. Notably, <b>P2</b> and <b>P13</b> significantly inhibited Poly(I:C)/IFNγ-induced inflammatory cytokines in human epidermal keratinocytes. Oral studies demonstrated favorable pharmacokinetics releasing micromolar concentrations of IA or 4-MI from <b>P2</b> and <b>P13</b>, respectively. These findings highlight the potential of prodrug strategies to enhance itaconate’s cellular permeability and oral bioavailability, paving the way for clinical translation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"15 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026964","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 : 2025-01-23DOI: 10.1021/acs.jmedchem.4c02715
Fabao Zhao, Unai Atxabal, Sofia Mariottini, Feng Yi, James S. Lotti, Michael S. Layeux, Chandler Currier, Matthew P. Maderia, Lauren E. Cornelison, Carly M. Anderson, Eric P. Schultz, Zhucheng Zhang, Liyang Jiang, Zhen Gao, Na Liu, Erica L. Woodahl, Lennart Bunch, Kasper B. Hansen, Rasmus P. Clausen
NMDA receptor ligands have therapeutic potential in neurological and psychiatric disorders. We designed (R)-3-(5-thienyl)carboxamido-2-aminopropanoic acid derivatives with nanomolar agonist potencies at NMDA receptor subtypes (GluN12/A-D). These compounds are superagonists at GluN1/2C compared to glycine and partial to full agonists at GluN1/2A and GluN1/2D but display functional antagonism at GluN1/2B due to low agonist efficacy. Notably, 8d display 864% agonist efficacy at GluN1/2C relative to glycine, and 8j has high potency at GluN1/2A (0.018 μM), GluN1/2C (0.0029 μM), and GluN1/2D (0.016 μM). We evaluated the binding mode in the glycine site using molecular modeling and mutagenesis. In vitro absorption, distribution, metabolism, and excretion (ADME) assays predict high metabolic stability but poor blood–brain barrier permeability. However, an ester prodrug for the carboxylate group of 7j display moderately high blood–brain barrier permeability. The thiophenecarboxamide agonists expand the synthetic pharmacology of NMDA receptors and provide structural insights that facilitate the design of GluN1 agonists with GluN2 subunit-specific activity.
{"title":"Design of (R)-3-(5-Thienyl)carboxamido-2-aminopropanoic Acid Derivatives as Novel NMDA Receptor Glycine Site Agonists: Variation in Molecular Geometry to Improve Potency and Augment GluN2 Subunit-Specific Activity","authors":"Fabao Zhao, Unai Atxabal, Sofia Mariottini, Feng Yi, James S. Lotti, Michael S. Layeux, Chandler Currier, Matthew P. Maderia, Lauren E. Cornelison, Carly M. Anderson, Eric P. Schultz, Zhucheng Zhang, Liyang Jiang, Zhen Gao, Na Liu, Erica L. Woodahl, Lennart Bunch, Kasper B. Hansen, Rasmus P. Clausen","doi":"10.1021/acs.jmedchem.4c02715","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02715","url":null,"abstract":"NMDA receptor ligands have therapeutic potential in neurological and psychiatric disorders. We designed (<i>R</i>)-3-(5-thienyl)carboxamido-2-aminopropanoic acid derivatives with nanomolar agonist potencies at NMDA receptor subtypes (GluN12/A-D). These compounds are superagonists at GluN1/2C compared to glycine and partial to full agonists at GluN1/2A and GluN1/2D but display functional antagonism at GluN1/2B due to low agonist efficacy. Notably, <b>8d</b> display 864% agonist efficacy at GluN1/2C relative to glycine, and <b>8j</b> has high potency at GluN1/2A (0.018 μM), GluN1/2C (0.0029 μM), and GluN1/2D (0.016 μM). We evaluated the binding mode in the glycine site using molecular modeling and mutagenesis. <i>In vitro</i> absorption, distribution, metabolism, and excretion (ADME) assays predict high metabolic stability but poor blood–brain barrier permeability. However, an ester prodrug for the carboxylate group of <b>7j</b> display moderately high blood–brain barrier permeability. The thiophenecarboxamide agonists expand the synthetic pharmacology of NMDA receptors and provide structural insights that facilitate the design of GluN1 agonists with GluN2 subunit-specific activity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"8 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026985","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}
The death signaling complex comprising extrasynaptic NMDAR and TRPM4 plays a pivotal role in the pathogenesis of ischemic stroke. Targeting the protein-protein interactions between NMDAR and TRPM4 represents a promising therapeutic strategy for ischemic stroke. Herein, we describe the discovery of a novel series of NMDAR/TRPM4 interaction interface inhibitors aimed at enhancing neuroprotective efficacy and optimizing pharmacokinetic profiles. The representative compound HZS60 displayed significant neuroprotective effects against both NMDA and oxygen-glucose deprivation/reoxygenation-induced ischemic injury in primary neurons. Notably, HZS60 exhibited a favorable pharmacokinetic profile and excellent brain permeability. Furthermore, HZS60 provided effective neuroprotection following brain ischemia and reperfusion injury in vivo. Collectively, these findings underscore the potential of HZS60 as a promising candidate for the development of novel therapeutic strategies for ischemic stroke.
{"title":"Discovery of HZS60 as a Novel Brain Penetrant NMDAR/TRPM4 Interaction Interface Inhibitor with Improved Activity and Pharmacokinetic Properties for the Treatment of Cerebral Ischemia.","authors":"Meiling Sun, Lin Wang, Qiaofeng Cao, Xuechun Wang, Ying Zhang, Manyu Guo, Jie Chen, Yuchen Ma, Le Niu, Yanping Zhang, Mengdie Hu, Mengli Gu, Zhihui Zhu, Xinyi Yao, Junchen Yao, Chen Zhao, Jin Wu, Xiuxiu Liu, Yingmei Lu, Zhen Wang, Qiuping Xiang, Feng Han, Dongsheng Zhu","doi":"10.1021/acs.jmedchem.4c02772","DOIUrl":"10.1021/acs.jmedchem.4c02772","url":null,"abstract":"<p><p>The death signaling complex comprising extrasynaptic NMDAR and TRPM4 plays a pivotal role in the pathogenesis of ischemic stroke. Targeting the protein-protein interactions between NMDAR and TRPM4 represents a promising therapeutic strategy for ischemic stroke. Herein, we describe the discovery of a novel series of NMDAR/TRPM4 interaction interface inhibitors aimed at enhancing neuroprotective efficacy and optimizing pharmacokinetic profiles. The representative compound <b>HZS60</b> displayed significant neuroprotective effects against both NMDA and oxygen-glucose deprivation/reoxygenation-induced ischemic injury in primary neurons. Notably, <b>HZS60</b> exhibited a favorable pharmacokinetic profile and excellent brain permeability. Furthermore, <b>HZS60</b> provided effective neuroprotection following brain ischemia and reperfusion injury <i>in vivo</i>. Collectively, these findings underscore the potential of <b>HZS60</b> as a promising candidate for the development of novel therapeutic strategies for ischemic stroke.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"2008-2043"},"PeriodicalIF":6.8,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913249","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}
Pyroptosis, an excellent form of immunogenic cell death that can effectively activate antitumor immune responses, is attracting considerable interest as a promising approach for cancer immunotherapy. Immunogenic pyroptosis can recruit and stimulate dendritic cells to provoke further activation and tumor infiltration of T cells by releasing danger-associated molecular patterns, thus improving the tumor response to PD-1/PD-L1 checkpoint blockade immunotherapy. Here, we report the discovery of a bifunctional photosensitizer Nile Violet that can simultaneously trigger caspase-3/GSDME-mediated immunogenic pyroptosis and PD-L1 downregulation for cancer photoimmunotherapy. It was shown that this synergistic therapeutic strategy significantly inhibited tumor growth by triggering a systemic antitumor immune response. This work highlights the potential of inducing immunogenic pyroptosis and PD-L1 downregulation for synergistic tumor ablation via a single agent.
{"title":"Simultaneous Induction of Immunogenic Pyroptosis and PD-L1 Downregulation by One Single Photosensitizer for Synergistic Cancer Photoimmunotherapy","authors":"Weijia Chen, Jingru Qiu, Peixia Li, Qianqian Zhang, Donghai Li, Guiling Li, Gang Shan","doi":"10.1021/acs.jmedchem.4c02747","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02747","url":null,"abstract":"Pyroptosis, an excellent form of immunogenic cell death that can effectively activate antitumor immune responses, is attracting considerable interest as a promising approach for cancer immunotherapy. Immunogenic pyroptosis can recruit and stimulate dendritic cells to provoke further activation and tumor infiltration of T cells by releasing danger-associated molecular patterns, thus improving the tumor response to PD-1/PD-L1 checkpoint blockade immunotherapy. Here, we report the discovery of a bifunctional photosensitizer Nile Violet that can simultaneously trigger caspase-3/GSDME-mediated immunogenic pyroptosis and PD-L1 downregulation for cancer photoimmunotherapy. It was shown that this synergistic therapeutic strategy significantly inhibited tumor growth by triggering a systemic antitumor immune response. This work highlights the potential of inducing immunogenic pyroptosis and PD-L1 downregulation for synergistic tumor ablation via a single agent.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"38 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026988","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 : 2025-01-23DOI: 10.1021/acs.jmedchem.4c02329
Biao Yang, Changyu Shan, Xiaoying Lv, Xiangming Song, Dexing Zeng, Rui An, Xiaoli Lan, Yongkang Gai
Radiopharmaceutical theranostics holds significant promise in tumor diagnosis and treatment, but suboptimal tumor uptake and retention remain a persistent limitation. We have conjugated a unique albumin binder to our previously developed heterodimeric precursor HX01 and achieved a novel precursor L6, aiming to prolong circulation time and enhance tumor accumulation and retention. However, we observed that the NGR sequence of L6 was gradually rearranged to iso-DGR under alkaline conditions, resulting in decreased stability. In this study, we further modified the L6 to synthesize XH02, subsequently assessing their in vitro and in vivo properties following radiolabeling. Utilizing positron emission tomography (PET)/computed tomography (CT) imaging, single-photon emission computed tomography (SPECT)/CT imaging, and biodistribution study in BxPC-3 xenograft mice, we observed striking accumulation and retention of radiopharmaceutical within tumors. Two cycles of administration of 177Lu-XH02 displayed exceptional tumor growth inhibition in BxPC-3 tumors while causing minimal side effects. This promising result underscores the immense potential of this agent for further clinical translation and investigation.
{"title":"177Lu-Labeled Heterodimeric Agent with High Stability Targeting Neovascularization for Tumor Radioligand Therapy","authors":"Biao Yang, Changyu Shan, Xiaoying Lv, Xiangming Song, Dexing Zeng, Rui An, Xiaoli Lan, Yongkang Gai","doi":"10.1021/acs.jmedchem.4c02329","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02329","url":null,"abstract":"Radiopharmaceutical theranostics holds significant promise in tumor diagnosis and treatment, but suboptimal tumor uptake and retention remain a persistent limitation. We have conjugated a unique albumin binder to our previously developed heterodimeric precursor HX01 and achieved a novel precursor L6, aiming to prolong circulation time and enhance tumor accumulation and retention. However, we observed that the NGR sequence of L6 was gradually rearranged to iso-DGR under alkaline conditions, resulting in decreased stability. In this study, we further modified the L6 to synthesize XH02, subsequently assessing their <i>in vitro</i> and <i>in vivo</i> properties following radiolabeling. Utilizing positron emission tomography (PET)/computed tomography (CT) imaging, single-photon emission computed tomography (SPECT)/CT imaging, and biodistribution study in BxPC-3 xenograft mice, we observed striking accumulation and retention of radiopharmaceutical within tumors. Two cycles of administration of <sup>177</sup>Lu-XH02 displayed exceptional tumor growth inhibition in BxPC-3 tumors while causing minimal side effects. This promising result underscores the immense potential of this agent for further clinical translation and investigation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"50 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020378","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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