The authors have noticed that the GAPDH panel in Figure 2A and Figures 6A (Phase I detoxyfying enzymes) and 6B (Phase II detoxyfying enzymes) are identical, which has led us to rectify the GAPDH in the revised Figures 6A and 6B. The error in the figure occurred unintentionally during the electronic transfer of the original image files, which were placed in the final Figures 6A and 6B. The rectification of this error does not affect the results or conclusions, as the heat map created using a gradient color scale (densitometry) shown in the figure is indeed based on the original GAPDH (Figure 6A and 6B). All other data published in this article are correct. The supporting data included in the supplementary file (Table S6) will also remain the same as the calculations and the statistical analyses were performed using the original GAPDH. Figure 6. Assessment of the safety profile of CQFC1 toward the host cells, in vivo. (A, B) CQFC1 did not alter phase I (A) and phase II (B) detoxification enzyme components in the host liver, in vivo. Each sample was amplified for mouse GAPDH to ensure equal cDNA input. The densitometry was analyzed by Image Lab software and is represented in heat maps using a gradient color scale. Each square in the heat map represents the mean value of fold changes of respective detoxification enzymes normalized against the expression of GAPDH; the statistical analyses (mean ± SEM and p values) are presented in Supporting Information Table S6. GraphPad Prism software (v 8.0) was used to generate the heat maps from experiments performed in duplicate. (C, D) CQFC1 did not promote oxidative stress as the levels of the antioxidants [SOD and CAT (C; *p < 0.001 vs infection)] and lipid peroxidation products (D; *p < 0.001 vs infection) remained unchanged with respect to the uninfected state (C, D; p > 0.05 vs naive animals). (E–G) CQFC1 had no cytotoxic effect on murine organs also, as seen by the levels of serum biomarker enzymes specific for hepatotoxicity (E; *p < 0.001 vs infection), cardiotoxicity (F; *p < 0.001 vs infection), and nephrotoxicity (G; *p < 0.001 vs infection) with respect to uninfected controls (E–G; p > 0.05 vs naive animals). Scatter plots were prepared using GraphPad Prism software from the cumulative data obtained from at least 5 animals per experimental group in duplicate (uninfected: green; infected: red; oral dose 2: sky blue; and intramuscular dose 2: deep blue). One-way ANOVA followed by Dunnett’s post hoc test was used to compare the variations in means between experimental groups. This article has not yet been cited by other publications.
{"title":"Correction to “Targeting the Trypanothione Reductase of Tissue-Residing Leishmania in Hosts’ Reticuloendothelial System: A Flexible Water-Soluble Ferrocenylquinoline-Based Preclinical Drug Candidate”","authors":"Debarati Mukherjee, Md Yousuf, Somaditya Dey, Sondipon Chakraborty, Ankur Chaudhuri, Vinay Kumar, Biswajyoti Sarkar, Supriya Nath, Aabid Hussain, Aritri Dutta, Tanushree Mishra, Biswajit Gopal Roy, Sushma Singh, Sibani Chakraborty, Susanta Adhikari, Chiranjib Pal","doi":"10.1021/acs.jmedchem.5c00610","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00610","url":null,"abstract":"The authors have noticed that the GAPDH panel in Figure 2A and Figures 6A (Phase I detoxyfying enzymes) and 6B (Phase II detoxyfying enzymes) are identical, which has led us to rectify the GAPDH in the revised Figures 6A and 6B. The error in the figure occurred unintentionally during the electronic transfer of the original image files, which were placed in the final Figures 6A and 6B. The rectification of this error does not affect the results or conclusions, as the heat map created using a gradient color scale (densitometry) shown in the figure is indeed based on the original GAPDH (Figure 6A and 6B). All other data published in this article are correct. The supporting data included in the supplementary file (Table S6) will also remain the same as the calculations and the statistical analyses were performed using the original GAPDH. Figure 6. Assessment of the safety profile of CQFC1 toward the host cells, <i>in vivo.</i> (A, B) CQFC1 did not alter phase I (A) and phase II (B) detoxification enzyme components in the host liver, <i>in vivo.</i> Each sample was amplified for mouse GAPDH to ensure equal cDNA input. The densitometry was analyzed by Image Lab software and is represented in heat maps using a gradient color scale. Each square in the heat map represents the mean value of fold changes of respective detoxification enzymes normalized against the expression of GAPDH; the statistical analyses (mean ± SEM and <i>p</i> values) are presented in Supporting Information Table S6. GraphPad Prism software (v 8.0) was used to generate the heat maps from experiments performed in duplicate. (C, D) CQFC1 did not promote oxidative stress as the levels of the antioxidants [SOD and CAT (C; *<i>p</i> < 0.001 vs infection)] and lipid peroxidation products (D; *<i>p</i> < 0.001 vs infection) remained unchanged with respect to the uninfected state (C, D; <i>p</i> > 0.05 vs naive animals). (E–G) CQFC1 had no cytotoxic effect on murine organs also, as seen by the levels of serum biomarker enzymes specific for hepatotoxicity (E; *<i>p</i> < 0.001 vs infection), cardiotoxicity (F; *<i>p</i> < 0.001 vs infection), and nephrotoxicity (G; *<i>p</i> < 0.001 vs infection) with respect to uninfected controls (E–G; <i>p</i> > 0.05 vs naive animals). Scatter plots were prepared using GraphPad Prism software from the cumulative data obtained from at least 5 animals per experimental group in duplicate (uninfected: green; infected: red; oral dose 2: sky blue; and intramuscular dose 2: deep blue). One-way ANOVA followed by Dunnett’s post hoc test was used to compare the variations in means between experimental groups. This article has not yet been cited by other publications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"56 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745258","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 : 2025-03-31DOI: 10.1021/acs.jmedchem.4c02697
Yunhan Jiang, Meng Zhou, Mengdi Cheng, Dongmei Fan, Weiqing Jiang, Xinyuan Fu, Yingqiang Guo, Tao Yang
Adapter switches are commonly developed to control the activation process of CAR-T cells. However, these affinity-based adapter switches cannot control the exhaustion level of CAR-T cells, which leads to a reduction of antitumor activity. To overcome this hurdle, we developed a CAR system based on split intein-mediated protein trans-splicing. In this system, a split C-intein-mediated adapter switch (SIMAS) containing a CD19 antibody splices with an N-intein motif engineered on T-cell receptors to incorporate CD19 antibodies into T-cell receptors site-specifically, which generates protein trans-splicing-based integrated CAR-T (protinCAR-T) cells. Importantly, trans-splicing does not activate CAR-T cells, thus reducing exhaustion level. Only the binding of protinCAR-T cells to tumor cells and cell motility activate protinCAR-T cells, which have good antitumor activity in vivo. Generally, we developed a novel CAR system that enables tuning of CAR-T-cell activity, which provides solutions to address the safety and efficacy barriers of CAR-T-cell therapy.
{"title":"Universal Protein Trans-Splicing-Based CAR System Enabling CAR-T Cells with Reduced Exhaustion and Enhanced Efficacy","authors":"Yunhan Jiang, Meng Zhou, Mengdi Cheng, Dongmei Fan, Weiqing Jiang, Xinyuan Fu, Yingqiang Guo, Tao Yang","doi":"10.1021/acs.jmedchem.4c02697","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02697","url":null,"abstract":"Adapter switches are commonly developed to control the activation process of CAR-T cells. However, these affinity-based adapter switches cannot control the exhaustion level of CAR-T cells, which leads to a reduction of antitumor activity. To overcome this hurdle, we developed a CAR system based on split intein-mediated protein trans-splicing. In this system, a split C-intein-mediated adapter switch (SIMAS) containing a CD19 antibody splices with an N-intein motif engineered on T-cell receptors to incorporate CD19 antibodies into T-cell receptors site-specifically, which generates protein trans-splicing-based integrated CAR-T (protinCAR-T) cells. Importantly, trans-splicing does not activate CAR-T cells, thus reducing exhaustion level. Only the binding of protinCAR-T cells to tumor cells and cell motility activate protinCAR-T cells, which have good antitumor activity in vivo. Generally, we developed a novel CAR system that enables tuning of CAR-T-cell activity, which provides solutions to address the safety and efficacy barriers of CAR-T-cell therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745224","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 : 2025-03-31DOI: 10.1021/acs.jmedchem.5c00112
Jonah Pascal Propp, Damien Oz Castor, M. Ashley Spies
In an era of escalating antibiotic resistance, there is a pressing need for innovative strategies to develop novel antibiotics. Gram-negative bacteria, characterized by their robust dual-membrane, are intrinsically resistant to a wide range of antibiotics and can readily develop new resistances. Members of this bacterial class comprise numerous pathogenic organisms, including the primary cause of gastric cancer, Helicobacter pylori. In this study, we used the Giga-sized collection of theoretical molecules inside Enamine’s REAL Space to identify inhibitors for H. pylori glutamate racemase. These compounds displayed a diverse range of activity in preventing H. pylori growth, with our most potent hits capable of selective full growth inhibition for metronidazole and clarithromycin resistant H. pylori strains. Alongside the introduction of a novel antibiotic class for this carcinogenic pathogen, our unique implementation of REAL Space holds great promise for Gram-negative antibiotic development as a whole.
{"title":"Real Way to Target Gram-Negative Pathogens: Discovery of a Novel Helicobacter pylori Antibiotic Class","authors":"Jonah Pascal Propp, Damien Oz Castor, M. Ashley Spies","doi":"10.1021/acs.jmedchem.5c00112","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00112","url":null,"abstract":"In an era of escalating antibiotic resistance, there is a pressing need for innovative strategies to develop novel antibiotics. Gram-negative bacteria, characterized by their robust dual-membrane, are intrinsically resistant to a wide range of antibiotics and can readily develop new resistances. Members of this bacterial class comprise numerous pathogenic organisms, including the primary cause of gastric cancer, <i>Helicobacter pylori</i>. In this study, we used the Giga-sized collection of theoretical molecules inside Enamine’s REAL Space to identify inhibitors for <i>H. pylori</i> glutamate racemase. These compounds displayed a diverse range of activity in preventing <i>H. pylori</i> growth, with our most potent hits capable of selective full growth inhibition for metronidazole and clarithromycin resistant <i>H. pylori</i> strains. Alongside the introduction of a novel antibiotic class for this carcinogenic pathogen, our unique implementation of REAL Space holds great promise for Gram-negative antibiotic development as a whole.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"183 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745256","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 : 2025-03-31DOI: 10.1021/acs.jmedchem.4c02942
Ramon G. de Oliveira, Luiza R. Cruz, Marco A. Dessoy, Paul J. Koovits, Deborah A. dos Santos, Luiz F. N. de Oliveira, Rafael A. Ferreira, María C. Mollo, Eun Lee, Simone M. Duarte, Renata Krogh, Leonardo L. G. Ferreira, Rafael C. Chelucci, Maria Dichiara, Quillon J. Simpson, Clarissa Feltrin, Adriana C. da Silva, Benedito M. dos Santos, Milena F. Broering, Michael P. Pollastri, Lori Ferrins, Carolina B. Moraes, Adriano D. Andricopulo, Jadel M. Kratz, Peter Sjö, Charles E. Mowbray, Luiz C. Dias
Chagas disease (CD), caused by the flagellate protozoan Trypanosoma cruzi, is a neglected tropical disease endemic in 21 countries. The only two antiparasitic drugs approved for its treatment, benznidazole and nifurtimox, have significant drawbacks. We present herein the optimization of a series of substituted indoles that were identified through phenotypic screening against T. cruzi. Early lead compounds with balanced potency and physicochemical properties were advanced to animal studies but showed limited plasma exposure. Medicinal chemistry strategies were used to improve metabolic stability and solubility, but unfortunately, this effort failed to yield compounds with improvements in both exposure and potency. Still, the best compound was progressed for a proof-of-concept efficacy study using acute and chronic mice models of Chagas disease. Despite showing antiparasitic activity in these in vivo studies, the optimization work with this series was stopped due to unfavorable drug metabolism and pharmacokinetic (DMPK) properties and a deprioritized mechanism of action (CYP51 inhibition).
{"title":"Discovery and Early Optimization of 1H-Indole-2-carboxamides with Anti-Trypanosoma cruzi Activity","authors":"Ramon G. de Oliveira, Luiza R. Cruz, Marco A. Dessoy, Paul J. Koovits, Deborah A. dos Santos, Luiz F. N. de Oliveira, Rafael A. Ferreira, María C. Mollo, Eun Lee, Simone M. Duarte, Renata Krogh, Leonardo L. G. Ferreira, Rafael C. Chelucci, Maria Dichiara, Quillon J. Simpson, Clarissa Feltrin, Adriana C. da Silva, Benedito M. dos Santos, Milena F. Broering, Michael P. Pollastri, Lori Ferrins, Carolina B. Moraes, Adriano D. Andricopulo, Jadel M. Kratz, Peter Sjö, Charles E. Mowbray, Luiz C. Dias","doi":"10.1021/acs.jmedchem.4c02942","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02942","url":null,"abstract":"Chagas disease (CD), caused by the flagellate protozoan <i>Trypanosoma cruzi</i>, is a neglected tropical disease endemic in 21 countries. The only two antiparasitic drugs approved for its treatment, benznidazole and nifurtimox, have significant drawbacks. We present herein the optimization of a series of substituted indoles that were identified through phenotypic screening against <i>T. cruzi</i>. Early lead compounds with balanced potency and physicochemical properties were advanced to animal studies but showed limited plasma exposure. Medicinal chemistry strategies were used to improve metabolic stability and solubility, but unfortunately, this effort failed to yield compounds with improvements in both exposure and potency. Still, the best compound was progressed for a proof-of-concept efficacy study using acute and chronic mice models of Chagas disease. Despite showing antiparasitic activity in these in vivo studies, the optimization work with this series was stopped due to unfavorable drug metabolism and pharmacokinetic (DMPK) properties and a deprioritized mechanism of action (CYP51 inhibition).","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"19 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745257","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 : 2025-03-31DOI: 10.1021/acs.jmedchem.5c00262
Sangita Dattatray Shinde, Ambika Chamoli, Sai Swetha Uppalapati, Jaidev Sharma, Vibhor Kumar, Amit Mandoli, Dinesh Kumar
Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis, especially when diagnosed late. Around 10–15% of cases involve the specific chromosomal abnormality t(8;21), which drives uncontrolled myeloid cell proliferation and contributes to disease onset. Despite advances in AML research and treatment protocols, outcomes for t(8;21) AML remain stagnant, as patients receive standard, nonspecific chemotherapies. This one-size-fits-all approach targets both cancerous and healthy cells, leading to unwanted toxicity and highlighting the urgent need for targeted therapies. In this study, we present a precision chemotype based on a quinoxalone-tethered adamantane framework developed via a metal- and light-free protocol. The compound selectively inhibits t(8;21) AML cell proliferation and induces cell death by disrupting growth and metabolic pathways, as demonstrated through bioassays, RNA sequencing, and proteomic analysis. Notably, it spares other leukemic and solid cancer cells, underscoring its specificity and potential as a targeted therapy for t(8;21) AML.
{"title":"Adamantane-Quinoxalone Hybrids: Precision Chemotypes and Their Molecular Mechanisms in Acute Myeloid Leukemia","authors":"Sangita Dattatray Shinde, Ambika Chamoli, Sai Swetha Uppalapati, Jaidev Sharma, Vibhor Kumar, Amit Mandoli, Dinesh Kumar","doi":"10.1021/acs.jmedchem.5c00262","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00262","url":null,"abstract":"Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis, especially when diagnosed late. Around 10–15% of cases involve the specific chromosomal abnormality t(8;21), which drives uncontrolled myeloid cell proliferation and contributes to disease onset. Despite advances in AML research and treatment protocols, outcomes for t(8;21) AML remain stagnant, as patients receive standard, nonspecific chemotherapies. This one-size-fits-all approach targets both cancerous and healthy cells, leading to unwanted toxicity and highlighting the urgent need for targeted therapies. In this study, we present a precision chemotype based on a quinoxalone-tethered adamantane framework developed via a metal- and light-free protocol. The compound selectively inhibits t(8;21) AML cell proliferation and induces cell death by disrupting growth and metabolic pathways, as demonstrated through bioassays, RNA sequencing, and proteomic analysis. Notably, it spares other leukemic and solid cancer cells, underscoring its specificity and potential as a targeted therapy for t(8;21) AML.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"3 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745225","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 : 2025-03-31DOI: 10.1021/acs.jmedchem.4c02929
Charles W. Parry, Francesca Pellicano, Alexander W. Schüttelkopf, Kim S. Beyer, Justin Bower, Amy Bryson, Kenneth Cameron, Nichole M. Cerutti, Jonathan P. Clark, Stuart C. Davidson, Keneth Davies, Martin J. Drysdale, Jeffrey Engelman, Anna Estevan-Barber, Andrea Gohlke, Christopher H. Gray, Daniel A. Guthy, Min Hong, Alana Hopkins, Luke D. Hutchinson, Jennifer Konczal, Michel Maira, Duncan McArthur, Mokdad Mezna, Heather McKinnon, Ridvan Nepravishta, Nils Ostermann, Camila C. Pasquali, Katie Pollock, Angelo Pugliese, Nicholas Rooney, Niko Schmiedeberg, Paul Shaw, Camilo Velez-Vega, Christopher West, Ryan West, Frederic Zecri, John B. Taylor
Activating mutations of Ras are one of the most prevalent drivers of cancer and are often associated with poor clinical outcomes. Despite FDA approval for two irreversible inhibitors that target the inactive state of KRasG12C, significant unmet clinical need still exists, and the susceptibility of non-G12C mutants to inactive-state inhibition remains unclear. Here we report the discovery of a novel series of reversible inhibitors that bind in an enlarged version of the switch I–II pocket with nanomolar affinities. Dependent on chemotype these can either preferentially bind to the inactive or active state or bind both with similar affinity. The active-state binders inhibit the Raf interaction for wild-type Ras, and a broad range of oncogenic KRas mutants with nanomolar potency. A subseries of these molecules displays cellular inhibition of Ras–Raf binding, as well as decreased phosphorylation of the downstream protein ERK, demonstrating that potent multivariant Ras inhibitors can be accessed from this novel pocket.
{"title":"Reversible Small Molecule Multivariant Ras Inhibitors Display Tunable Affinity for the Active and Inactive Forms of Ras","authors":"Charles W. Parry, Francesca Pellicano, Alexander W. Schüttelkopf, Kim S. Beyer, Justin Bower, Amy Bryson, Kenneth Cameron, Nichole M. Cerutti, Jonathan P. Clark, Stuart C. Davidson, Keneth Davies, Martin J. Drysdale, Jeffrey Engelman, Anna Estevan-Barber, Andrea Gohlke, Christopher H. Gray, Daniel A. Guthy, Min Hong, Alana Hopkins, Luke D. Hutchinson, Jennifer Konczal, Michel Maira, Duncan McArthur, Mokdad Mezna, Heather McKinnon, Ridvan Nepravishta, Nils Ostermann, Camila C. Pasquali, Katie Pollock, Angelo Pugliese, Nicholas Rooney, Niko Schmiedeberg, Paul Shaw, Camilo Velez-Vega, Christopher West, Ryan West, Frederic Zecri, John B. Taylor","doi":"10.1021/acs.jmedchem.4c02929","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02929","url":null,"abstract":"Activating mutations of Ras are one of the most prevalent drivers of cancer and are often associated with poor clinical outcomes. Despite FDA approval for two irreversible inhibitors that target the inactive state of KRas<sup>G12C</sup>, significant unmet clinical need still exists, and the susceptibility of non-G12C mutants to inactive-state inhibition remains unclear. Here we report the discovery of a novel series of reversible inhibitors that bind in an enlarged version of the switch I–II pocket with nanomolar affinities. Dependent on chemotype these can either preferentially bind to the inactive or active state or bind both with similar affinity. The active-state binders inhibit the Raf interaction for wild-type Ras, and a broad range of oncogenic KRas mutants with nanomolar potency. A subseries of these molecules displays cellular inhibition of Ras–Raf binding, as well as decreased phosphorylation of the downstream protein ERK, demonstrating that potent multivariant Ras inhibitors can be accessed from this novel pocket.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"183 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737121","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 : 2025-03-31DOI: 10.1021/acs.jmedchem.4c0246810.1021/acs.jmedchem.4c02468
Gabriel Lemieux, Jimena Pérez-Vargas, Antoine Désilets, Malihe Hassanzadeh, Connor A. H. Thompson, Alice Gravel-Trudeau, Alexandre Joushomme, Siobhan Ennis, Ivan Villanueva, Étienne Marouseau, Bryan J. Fraser, William Champagne, Matthieu Lepage, Masahiro Niikura, Cheryl H. Arrowsmith, François Jean*, Richard Leduc* and Pierre-Luc Boudreault*,
The worldwide spread of new SARS-CoV-2 variants emphasizes the need to diversify existing therapeutic strategies. TMPRSS2, a host protease crucial for SARS-CoV-2 entry, has garnered significant research attention as a potential target for therapeutic intervention. Here, we optimized N-0385, a previously reported TMPRSS2 ketobenzothiazole-based peptidomimetic inhibitor, by screening 135 derivatives for target affinity and antiviral potency. Among the top candidates, N-0695 exhibited low nanomolar Ki values against three TTSPs associated with respiratory virus entry: TMPRSS2, matriptase, and TMPRSS13. Notably, N-0920 demonstrated exceptional potency in reducing SARS-CoV-2 variants EG.5.1 and JN.1 entry in Calu-3 cells, representing the first in cellulo picomolar inhibitor with EC50 values of 300 and 90 pM, respectively. Additionally, molecular modeling provided insights into the binding interactions between the compounds and their targets. This study underscores the effectiveness of our screening approach in refining an existing peptidomimetic scaffold to enhance selectivity and antiviral activity.
{"title":"From N-0385 to N-0920: Unveiling a Host-Directed Protease Inhibitor with Picomolar Antiviral Efficacy against Prevalent SARS-CoV-2 Variants","authors":"Gabriel Lemieux, Jimena Pérez-Vargas, Antoine Désilets, Malihe Hassanzadeh, Connor A. H. Thompson, Alice Gravel-Trudeau, Alexandre Joushomme, Siobhan Ennis, Ivan Villanueva, Étienne Marouseau, Bryan J. Fraser, William Champagne, Matthieu Lepage, Masahiro Niikura, Cheryl H. Arrowsmith, François Jean*, Richard Leduc* and Pierre-Luc Boudreault*, ","doi":"10.1021/acs.jmedchem.4c0246810.1021/acs.jmedchem.4c02468","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02468https://doi.org/10.1021/acs.jmedchem.4c02468","url":null,"abstract":"<p >The worldwide spread of new SARS-CoV-2 variants emphasizes the need to diversify existing therapeutic strategies. TMPRSS2, a host protease crucial for SARS-CoV-2 entry, has garnered significant research attention as a potential target for therapeutic intervention. Here, we optimized N-0385, a previously reported TMPRSS2 ketobenzothiazole-based peptidomimetic inhibitor, by screening 135 derivatives for target affinity and antiviral potency. Among the top candidates, N-0695 exhibited low nanomolar <i>K</i><sub><i>i</i></sub> values against three TTSPs associated with respiratory virus entry: TMPRSS2, matriptase, and TMPRSS13. Notably, N-0920 demonstrated exceptional potency in reducing SARS-CoV-2 variants EG.5.1 and JN.1 entry in Calu-3 cells, representing the first in cellulo picomolar inhibitor with EC<sub>50</sub> values of 300 and 90 pM, respectively. Additionally, molecular modeling provided insights into the binding interactions between the compounds and their targets. This study underscores the effectiveness of our screening approach in refining an existing peptidomimetic scaffold to enhance selectivity and antiviral activity.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 7","pages":"7119–7136 7119–7136"},"PeriodicalIF":6.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806654","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 : 2025-03-31DOI: 10.1021/acs.jmedchem.4c0294210.1021/acs.jmedchem.4c02942
Ramon G. de Oliveira, Luiza R. Cruz, Marco A. Dessoy, Paul J. Koovits, Deborah A. dos Santos, Luiz F. N. de Oliveira, Rafael A. Ferreira, María C. Mollo, Eun Lee, Simone M. Duarte, Renata Krogh, Leonardo L. G. Ferreira, Rafael C. Chelucci, Maria Dichiara, Quillon J. Simpson, Clarissa Feltrin, Adriana C. da Silva, Benedito M. dos Santos, Milena F. Broering, Michael P. Pollastri, Lori Ferrins, Carolina B. Moraes, Adriano D. Andricopulo, Jadel M. Kratz, Peter Sjö, Charles E. Mowbray and Luiz C. Dias*,
Chagas disease (CD), caused by the flagellate protozoan Trypanosoma cruzi, is a neglected tropical disease endemic in 21 countries. The only two antiparasitic drugs approved for its treatment, benznidazole and nifurtimox, have significant drawbacks. We present herein the optimization of a series of substituted indoles that were identified through phenotypic screening against T. cruzi. Early lead compounds with balanced potency and physicochemical properties were advanced to animal studies but showed limited plasma exposure. Medicinal chemistry strategies were used to improve metabolic stability and solubility, but unfortunately, this effort failed to yield compounds with improvements in both exposure and potency. Still, the best compound was progressed for a proof-of-concept efficacy study using acute and chronic mice models of Chagas disease. Despite showing antiparasitic activity in these in vivo studies, the optimization work with this series was stopped due to unfavorable drug metabolism and pharmacokinetic (DMPK) properties and a deprioritized mechanism of action (CYP51 inhibition).
{"title":"Discovery and Early Optimization of 1H-Indole-2-carboxamides with Anti-Trypanosoma cruzi Activity","authors":"Ramon G. de Oliveira, Luiza R. Cruz, Marco A. Dessoy, Paul J. Koovits, Deborah A. dos Santos, Luiz F. N. de Oliveira, Rafael A. Ferreira, María C. Mollo, Eun Lee, Simone M. Duarte, Renata Krogh, Leonardo L. G. Ferreira, Rafael C. Chelucci, Maria Dichiara, Quillon J. Simpson, Clarissa Feltrin, Adriana C. da Silva, Benedito M. dos Santos, Milena F. Broering, Michael P. Pollastri, Lori Ferrins, Carolina B. Moraes, Adriano D. Andricopulo, Jadel M. Kratz, Peter Sjö, Charles E. Mowbray and Luiz C. Dias*, ","doi":"10.1021/acs.jmedchem.4c0294210.1021/acs.jmedchem.4c02942","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02942https://doi.org/10.1021/acs.jmedchem.4c02942","url":null,"abstract":"<p >Chagas disease (CD), caused by the flagellate protozoan <i>Trypanosoma cruzi</i>, is a neglected tropical disease endemic in 21 countries. The only two antiparasitic drugs approved for its treatment, benznidazole and nifurtimox, have significant drawbacks. We present herein the optimization of a series of substituted indoles that were identified through phenotypic screening against <i>T. cruzi</i>. Early lead compounds with balanced potency and physicochemical properties were advanced to animal studies but showed limited plasma exposure. Medicinal chemistry strategies were used to improve metabolic stability and solubility, but unfortunately, this effort failed to yield compounds with improvements in both exposure and potency. Still, the best compound was progressed for a proof-of-concept efficacy study using acute and chronic mice models of Chagas disease. Despite showing antiparasitic activity in these in vivo studies, the optimization work with this series was stopped due to unfavorable drug metabolism and pharmacokinetic (DMPK) properties and a deprioritized mechanism of action (CYP51 inhibition).</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 7","pages":"7313–7340 7313–7340"},"PeriodicalIF":6.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jmedchem.4c02942","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806782","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 : 2025-03-31DOI: 10.1021/acs.jmedchem.5c0026210.1021/acs.jmedchem.5c00262
Sangita Dattatray Shinde, Ambika Chamoli, Sai Swetha Uppalapati, Jaidev Sharma, Vibhor Kumar, Amit Mandoli* and Dinesh Kumar*,
Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis, especially when diagnosed late. Around 10–15% of cases involve the specific chromosomal abnormality t(8;21), which drives uncontrolled myeloid cell proliferation and contributes to disease onset. Despite advances in AML research and treatment protocols, outcomes for t(8;21) AML remain stagnant, as patients receive standard, nonspecific chemotherapies. This one-size-fits-all approach targets both cancerous and healthy cells, leading to unwanted toxicity and highlighting the urgent need for targeted therapies. In this study, we present a precision chemotype based on a quinoxalone-tethered adamantane framework developed via a metal- and light-free protocol. The compound selectively inhibits t(8;21) AML cell proliferation and induces cell death by disrupting growth and metabolic pathways, as demonstrated through bioassays, RNA sequencing, and proteomic analysis. Notably, it spares other leukemic and solid cancer cells, underscoring its specificity and potential as a targeted therapy for t(8;21) AML.
{"title":"Adamantane-Quinoxalone Hybrids: Precision Chemotypes and Their Molecular Mechanisms in Acute Myeloid Leukemia","authors":"Sangita Dattatray Shinde, Ambika Chamoli, Sai Swetha Uppalapati, Jaidev Sharma, Vibhor Kumar, Amit Mandoli* and Dinesh Kumar*, ","doi":"10.1021/acs.jmedchem.5c0026210.1021/acs.jmedchem.5c00262","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00262https://doi.org/10.1021/acs.jmedchem.5c00262","url":null,"abstract":"<p >Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis, especially when diagnosed late. Around 10–15% of cases involve the specific chromosomal abnormality t(8;21), which drives uncontrolled myeloid cell proliferation and contributes to disease onset. Despite advances in AML research and treatment protocols, outcomes for t(8;21) AML remain stagnant, as patients receive standard, nonspecific chemotherapies. This one-size-fits-all approach targets both cancerous and healthy cells, leading to unwanted toxicity and highlighting the urgent need for targeted therapies. In this study, we present a precision chemotype based on a quinoxalone-tethered adamantane framework developed via a metal- and light-free protocol. The compound selectively inhibits t(8;21) AML cell proliferation and induces cell death by disrupting growth and metabolic pathways, as demonstrated through bioassays, RNA sequencing, and proteomic analysis. Notably, it spares other leukemic and solid cancer cells, underscoring its specificity and potential as a targeted therapy for t(8;21) AML.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 7","pages":"7693–7706 7693–7706"},"PeriodicalIF":6.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806790","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 : 2025-03-31DOI: 10.1021/acs.jmedchem.4c0229110.1021/acs.jmedchem.4c02291
Jing Lu, Pengfei Yu, Yunjie Wang, Yusen Dai, Wenyan Wang, Chunjiao Liu, Lin Dong, Hui Lei, Yifei Yang, Lin Wang, Fangxia Zou, Xuan Deng, Bingsi Wang, Shujuan Wei, Mingxu Ma, Hongbo Wang, Liang Ye*, Jianzhao Zhang* and Jingwei Tian*,
The clinical-stage agonists for trace amine-associated receptor 1 (TAAR1) show insufficient clinical efficacy, requiring the design of new compounds beyond the TAAR1 receptor alone. Here, we provide evidence for the feasibility of designing TAAR1/5-HT2CR dual agonists based on structural basis of these two targets and similarities of their agonists. Three series of novel agonists were discovered, leading to a potent compound named 21b. 21b exhibits submicromolar potency on both TAAR1 and 5-HT2CR targets with high specificity confirmed by site-directed mutagenesis. Preclinical proof-of-concept studies showed that 21b was highly efficacious against the positive and negative symptoms of schizophrenia in mice models. 21b also alleviated cognitive deficits and psychoactive symptoms in Alzheimer’s disease (AD) model mice. Four week repeated dosing of 21b is exceptionally well tolerated in rats and beagle dogs without hyperglycemia commonly seen with antipsychotics. Thus, the favorable druggability of compound 21b warrants further clinical development for the treatment of schizophrenia and AD-related psychosis.
{"title":"Rational Design of the First Dual Agonist at Trace Amine-Associated Receptor 1 and 5-HT2C Receptors Based on Binding Pocket Similarity for the Treatment of Schizophrenia and Alzheimer’s Disease-Related Psychosis","authors":"Jing Lu, Pengfei Yu, Yunjie Wang, Yusen Dai, Wenyan Wang, Chunjiao Liu, Lin Dong, Hui Lei, Yifei Yang, Lin Wang, Fangxia Zou, Xuan Deng, Bingsi Wang, Shujuan Wei, Mingxu Ma, Hongbo Wang, Liang Ye*, Jianzhao Zhang* and Jingwei Tian*, ","doi":"10.1021/acs.jmedchem.4c0229110.1021/acs.jmedchem.4c02291","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02291https://doi.org/10.1021/acs.jmedchem.4c02291","url":null,"abstract":"<p >The clinical-stage agonists for trace amine-associated receptor 1 (TAAR1) show insufficient clinical efficacy, requiring the design of new compounds beyond the TAAR1 receptor alone. Here, we provide evidence for the feasibility of designing TAAR1/5-HT<sub>2C</sub>R dual agonists based on structural basis of these two targets and similarities of their agonists. Three series of novel agonists were discovered, leading to a potent compound named <b>21b</b>. <b>21b</b> exhibits submicromolar potency on both TAAR1 and 5-HT<sub>2C</sub>R targets with high specificity confirmed by site-directed mutagenesis. Preclinical proof-of-concept studies showed that <b>21b</b> was highly efficacious against the positive and negative symptoms of schizophrenia in mice models. <b>21b</b> also alleviated cognitive deficits and psychoactive symptoms in Alzheimer’s disease (AD) model mice. Four week repeated dosing of <b>21b</b> is exceptionally well tolerated in rats and beagle dogs without hyperglycemia commonly seen with antipsychotics. Thus, the favorable druggability of compound <b>21b</b> warrants further clinical development for the treatment of schizophrenia and AD-related psychosis.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 7","pages":"7082–7105 7082–7105"},"PeriodicalIF":6.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806649","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}