This work introduces a novel Pt(II) based prodrug TTFA-Platin that integrates a β-diketonate ligand TTFA with a platinum scaffold to structurally resemble carboplatin and offers intermediate kinetic lability between cisplatin and carboplatin, striking a balance between therapeutic efficacy and safety. A comprehensive stability and speciation study was conducted in various biological media, mapping the therapeutic effects of TTFA-Platin. A control molecule, TMK-Platin, was synthesized to further validate the structural-stability relationship, which displayed poor activatable features in biological systems. In vitro studies against a panel of cancer cell lines revealed that TTFA-Platin exhibited significantly higher potency compared to TMK-Platin. In vivo studies revealed that TTFA-Platin exhibited significantly lower toxicity than the reference platinum compounds. Thus, leveraging ligands that fine-tune kinetic lability and offer therapeutic benefits can help develop more effective and safer cancer treatments, addressing the limitations of existing therapies.
{"title":"TTFA-Platin Conjugate: Deciphering the Therapeutic Roles of Combo-Prodrug through Evaluating Stability-Activity Relationship.","authors":"Megha Biswas, Kanishka Chaudhary, Swati Shree Padhi, Arka Banerjee, R Selvi Bharathavikru, Sateesh Bandaru, Subhra Jyoti Panda, Chandra Shekhar Purohit, Nihar Ranjan Das, Rakesh Kumar Pathak","doi":"10.1021/acs.jmedchem.4c01545","DOIUrl":"10.1021/acs.jmedchem.4c01545","url":null,"abstract":"<p><p>This work introduces a novel Pt(II) based prodrug TTFA-Platin that integrates a β-diketonate ligand TTFA with a platinum scaffold to structurally resemble carboplatin and offers intermediate kinetic lability between cisplatin and carboplatin, striking a balance between therapeutic efficacy and safety. A comprehensive stability and speciation study was conducted in various biological media, mapping the therapeutic effects of TTFA-Platin. A control molecule, TMK-Platin, was synthesized to further validate the structural-stability relationship, which displayed poor activatable features in biological systems. <i>In vitro</i> studies against a panel of cancer cell lines revealed that TTFA-Platin exhibited significantly higher potency compared to TMK-Platin. <i>In vivo</i> studies revealed that TTFA-Platin exhibited significantly lower toxicity than the reference platinum compounds. Thus, leveraging ligands that fine-tune kinetic lability and offer therapeutic benefits can help develop more effective and safer cancer treatments, addressing the limitations of existing therapies.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"20986-21008"},"PeriodicalIF":6.8,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749376","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 : 2024-12-12DOI: 10.1021/acs.jmedchem.4c01405
Hideyuki Igawa, Zef A. Konst, Eric Therrien, Mee Shelley, Heidi Koldsø, Pieter H. Bos, Ana Negri, Andreas Verras, Jiaye Guo, Markus K. Dahlgren, Adam Levinson, Brendan T. Parr, Suresh E. Kurhade, Prashant Latthe, Rajesha Shetty, Sridhar Santhanakrishnan, Katherine Amberg-Johnson, Alan S. Futran, Christian Atsriku, Robert D. Pelletier, Zhijian Liu, Jeffrey A. Bell, Sathesh Bhat, Mats Svensson, Aleksey I. Gerasyuto
Despite the success of first, second, and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer with classical EGFR mutations (L858R or Exon 19 deletions), disease progression occurs due to the acquisition of T790M and C797S resistance. Herein, we report a physics-based computationally driven lead identification approach that identified structurally unique imidazo[3.2-b]pyrazoles as reversible and wild-type-sparing EGFR TKIs of classical mutations bearing both T790M and C797S. During profiling of imidazo[3.2-b]pyrazoles, we elucidated the bioactivation mechanism causing CYP3A4/5 time-dependent inhibition (TDI) and found key modifications to mitigate the TDI. Compound 31 inhibited EGFR L858R/T790M/C797S in biochemical assays with a Ki = 2.1 nM and EGFR del19/T790M/C797S in a Ba/F3 cellular assay with an IC50 = 56.9 nM. The deuterated analogue of 31 (38) demonstrated dose-dependent tumor growth inhibition in a Ba/F3 EGFR del19/T790M/C797S CDX model by 47% at 50 mg/kg BID and 92% at 100 mg/kg BID.
{"title":"Discovery of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using an In Silico Enabled Drug Discovery Platform","authors":"Hideyuki Igawa, Zef A. Konst, Eric Therrien, Mee Shelley, Heidi Koldsø, Pieter H. Bos, Ana Negri, Andreas Verras, Jiaye Guo, Markus K. Dahlgren, Adam Levinson, Brendan T. Parr, Suresh E. Kurhade, Prashant Latthe, Rajesha Shetty, Sridhar Santhanakrishnan, Katherine Amberg-Johnson, Alan S. Futran, Christian Atsriku, Robert D. Pelletier, Zhijian Liu, Jeffrey A. Bell, Sathesh Bhat, Mats Svensson, Aleksey I. Gerasyuto","doi":"10.1021/acs.jmedchem.4c01405","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01405","url":null,"abstract":"Despite the success of first, second, and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer with classical EGFR mutations (L858R or Exon 19 deletions), disease progression occurs due to the acquisition of T790M and C797S resistance. Herein, we report a physics-based computationally driven lead identification approach that identified structurally unique imidazo[3.2-<i>b</i>]pyrazoles as reversible and wild-type-sparing EGFR TKIs of classical mutations bearing both T790M and C797S. During profiling of imidazo[3.2-<i>b</i>]pyrazoles, we elucidated the bioactivation mechanism causing CYP3A4/5 time-dependent inhibition (TDI) and found key modifications to mitigate the TDI. Compound <b>31</b> inhibited EGFR L858R/T790M/C797S in biochemical assays with a <i>K</i><sub>i</sub> = 2.1 nM and EGFR del19/T790M/C797S in a Ba/F3 cellular assay with an IC<sub>50</sub> = 56.9 nM. The deuterated analogue of <b>31</b> (<b>38</b>) demonstrated dose-dependent tumor growth inhibition in a Ba/F3 EGFR del19/T790M/C797S CDX model by 47% at 50 mg/kg BID and 92% at 100 mg/kg BID.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"19 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816201","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 : 2024-12-12DOI: 10.1021/acs.jmedchem.4c02385
Dries Van Rompaey, Siladitya Ray Chaudhuri, Mazen Ahmad, Justin Cisar, An Van Den Bergh, Jeremy Ash, Zhe Wu, Marian C. Bryan, James P. Edwards, Renee DesJarlais, Jörg Kurt Wegner, Hugo Ceulemans, Kaushik Mitra, David Polidori
Human dose prediction (HDP) is a useful tool for compound optimization in preclinical drug discovery. We describe here our exclusively in silico HDP strategy to triage compound designs for synthesis and experimental profiling. Our goal is a model that provides a preliminary estimate of the dose for a given exposure target based on chemical structure. First, we construct machine learning models to estimate rat pharmacokinetics, which are subsequently allometrically scaled to estimate human pharmacokinetics. Second, we establish a 10 nM free concentration target for early HDP where potency data are not yet available. Finally, we assess the uncertainty associated with each model and propagate these into the final estimate, providing us with actionable guidance on the level of accuracy of these estimates. We find that this strategy can reduce preparation of compounds with poor properties relative to an unstructured approach, but extensive experimental testing remains required.
{"title":"Toward Dose Prediction at Point of Design","authors":"Dries Van Rompaey, Siladitya Ray Chaudhuri, Mazen Ahmad, Justin Cisar, An Van Den Bergh, Jeremy Ash, Zhe Wu, Marian C. Bryan, James P. Edwards, Renee DesJarlais, Jörg Kurt Wegner, Hugo Ceulemans, Kaushik Mitra, David Polidori","doi":"10.1021/acs.jmedchem.4c02385","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02385","url":null,"abstract":"Human dose prediction (HDP) is a useful tool for compound optimization in preclinical drug discovery. We describe here our exclusively in silico HDP strategy to triage compound designs for synthesis and experimental profiling. Our goal is a model that provides a preliminary estimate of the dose for a given exposure target based on chemical structure. First, we construct machine learning models to estimate rat pharmacokinetics, which are subsequently allometrically scaled to estimate human pharmacokinetics. Second, we establish a 10 nM free concentration target for early HDP where potency data are not yet available. Finally, we assess the uncertainty associated with each model and propagate these into the final estimate, providing us with actionable guidance on the level of accuracy of these estimates. We find that this strategy can reduce preparation of compounds with poor properties relative to an unstructured approach, but extensive experimental testing remains required.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"51 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816206","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 : 2024-12-12DOI: 10.1021/acs.jmedchem.4c01578
Barbara Mordyl, Nikola Fajkis-Zajączkowska, Katarzyna Szafrańska, Agata Siwek, Monika Głuch-Lutwin, Paweł Żmudzki, Jakub Jończyk, Tadeusz Karcz, Karolina Słoczyńska, Elżbieta Pękala, Bartosz Pomierny, Weronika Krzyżanowska, Jakub Jurczyk, Alicja Skórkowska, Aleksandra Sałach, Magdalena Jastrzębska-Więsek, Maria Walczak, Maciej Tadeusz Gawlik, Magdalena Smolik, Marcin Kolaczkowski, Monika Marcinkowska
Selective enhancement of synaptic GABA signaling mediated by GABA-A receptors has been previously reported to promote functional recovery after ischemic stroke, while tonic GABA signaling has been detrimental. To identify agents that enhance synaptic signaling, we synthesized GABA-A ligands based on three chemotypes with affinity values pKi= 6.44–8.32. Representative compounds showed a preference in functional responses toward synaptic type of GABA-A receptors, compared to the extrasynaptic ones. In a cellular ischemia model (OGD), selected compounds showed the potential to improve neuronal recovery. The selected lead, compound 4, demonstrated the ability to reduce mitochondrial dysfunction, regulate intracellular calcium levels, decrease caspase 3 levels, and promote neurite outgrowth in in vitro assays. In an animal model, compound 4 enhanced motor recovery and showed neuroprotective activity by reducing infarct volume and decreasing poststroke acidosis. These findings underscore the value of selective ligands modulating synaptic GABA-A receptors in promoting recovery from ischemic stroke.
{"title":"Preferential Synaptic Type of GABA-A Receptor Ligands Enhancing Neuronal Survival and Facilitating Functional Recovery After Ischemic Stroke","authors":"Barbara Mordyl, Nikola Fajkis-Zajączkowska, Katarzyna Szafrańska, Agata Siwek, Monika Głuch-Lutwin, Paweł Żmudzki, Jakub Jończyk, Tadeusz Karcz, Karolina Słoczyńska, Elżbieta Pękala, Bartosz Pomierny, Weronika Krzyżanowska, Jakub Jurczyk, Alicja Skórkowska, Aleksandra Sałach, Magdalena Jastrzębska-Więsek, Maria Walczak, Maciej Tadeusz Gawlik, Magdalena Smolik, Marcin Kolaczkowski, Monika Marcinkowska","doi":"10.1021/acs.jmedchem.4c01578","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01578","url":null,"abstract":"Selective enhancement of synaptic GABA signaling mediated by GABA-A receptors has been previously reported to promote functional recovery after ischemic stroke, while tonic GABA signaling has been detrimental. To identify agents that enhance synaptic signaling, we synthesized GABA-A ligands based on three chemotypes with affinity values p<i>K</i><sub>i</sub>= 6.44–8.32. Representative compounds showed a preference in functional responses toward synaptic type of GABA-A receptors, compared to the extrasynaptic ones. In a cellular ischemia model (OGD), selected compounds showed the potential to improve neuronal recovery. The selected lead, compound <b>4</b>, demonstrated the ability to reduce mitochondrial dysfunction, regulate intracellular calcium levels, decrease caspase 3 levels, and promote neurite outgrowth in <i>in vitro</i> assays. In an animal model, compound <b>4</b> enhanced motor recovery and showed neuroprotective activity by reducing infarct volume and decreasing poststroke acidosis. These findings underscore the value of selective ligands modulating synaptic GABA-A receptors in promoting recovery from ischemic stroke.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"93 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816202","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 : 2024-12-12DOI: 10.1021/acs.jmedchem.4c02898
Patrick Papa, Brandon Whitefield, Deborah S. Mortensen, Dan Cashion, Dehua Huang, Eduardo Torres, Jason Parnes, John Sapienza, Joshua Hansen, Matthew Correa, Mercedes Delgado, Roy Harris, Sayee Hegde, Stephen Norris, Sogole Bahmanyar, Veronique Plantevin-Krenitsky, Zheng Liu, Katerina Leftheris, Ashutosh Kulkarni, Brydon Bennett, Eun Mi Hur, Garth Ringheim, Godrej Khambatta, Henry Chan, Jeffrey Muir, Kate Blease, Kelven Burnett, Laurie LeBrun, Lisa Morrison, Maria Celeridad, Roli Khattri, Brian E. Cathers
In Figure 3 and the related text, Asp508 was incorrectly labeled as Asp409 due to typographical error in figure preparation. The corrected figure and updated line of text are as follow: Figure 3. Docking model of 3 bound in the ATP pocket of PKC-θ (PDB ID 1XJD used for docking studies). Page 11889: “The basic piperidine amine forms two salt-bridges with side-chain carboxylates of Asp465 and catalytic residue Asp522 and forms a third hydrogen bond to the backbone carbonyl of Asp508.” This article has not yet been cited by other publications.
{"title":"Correction to “Discovery of the Selective Protein Kinase C-θ Kinase Inhibitor, CC-90005”","authors":"Patrick Papa, Brandon Whitefield, Deborah S. Mortensen, Dan Cashion, Dehua Huang, Eduardo Torres, Jason Parnes, John Sapienza, Joshua Hansen, Matthew Correa, Mercedes Delgado, Roy Harris, Sayee Hegde, Stephen Norris, Sogole Bahmanyar, Veronique Plantevin-Krenitsky, Zheng Liu, Katerina Leftheris, Ashutosh Kulkarni, Brydon Bennett, Eun Mi Hur, Garth Ringheim, Godrej Khambatta, Henry Chan, Jeffrey Muir, Kate Blease, Kelven Burnett, Laurie LeBrun, Lisa Morrison, Maria Celeridad, Roli Khattri, Brian E. Cathers","doi":"10.1021/acs.jmedchem.4c02898","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02898","url":null,"abstract":"In Figure 3 and the related text, Asp508 was incorrectly labeled as Asp409 due to typographical error in figure preparation. The corrected figure and updated line of text are as follow:<named-content content-type=\"anchor\" r type=\"simple\"></named-content> Figure 3. Docking model of <b>3</b> bound in the ATP pocket of PKC-θ (PDB ID 1XJD used for docking studies). Page 11889: “The basic piperidine amine forms two salt-bridges with side-chain carboxylates of Asp465 and catalytic residue Asp522 and forms a third hydrogen bond to the backbone carbonyl of Asp508.” This article has not yet been cited by other publications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142810028","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 : 2024-12-12DOI: 10.1021/acs.jmedchem.4c02359
Kirsten Dahl, Kirsten Raun, Jakob Lerche Hansen, Christian Poulsen, Charlotta D. de la Cour, Trine Ryberg Clausen, Ann Maria Kruse Hansen, Linu M. John, Annette Plesner, Gao Sun, Morten Schlein, Rikke Bjerring Skyggebjerg, Thomas Kruse
Correction: The following paragraph previously on page 11691 is now the footnote for Table 12 on page 11693. “Data are mean ± SEM measured as percent food intake relative to vehicle in rats after a single sc injection of 30 nmol/kg of the test substance. Data for cagrilintide have been published previously7 giving rise to 85% and 84% reduction of food intake in the periods from 0–24 h and 24–48 h, respectively. SEM is the standard error of the mean.” Correction: The following paragraph was previously included as the footnotes for Table 9 on page 11692 and has been moved to page 11691. “From the in vitro data (Tables 10 and 11), it was apparent that selectivity was achieved for several peptides (10, 14, 15, 16, 17, 18, 20, and 21). From the ThT assay (Table 9 and Supporting Information), only three of the AMYR selective peptides (14, 16, and 21) were able to resist physical stress for more than 40 h. Two peptides (15 and 21) had a selectivity ratio above 30. Peptide 6 and peptides 11–21 with neutral/high pI were chosen for further evaluation in vivo to evaluate their ability to reduce food intake in rats after a single administration and to have increased insights into the duration of effects from the peptides in vivo (Table 11).” This article has not yet been cited by other publications.
{"title":"Correction to “NN1213 – A Potent, Long-Acting, and Selective Analog of Human Amylin”","authors":"Kirsten Dahl, Kirsten Raun, Jakob Lerche Hansen, Christian Poulsen, Charlotta D. de la Cour, Trine Ryberg Clausen, Ann Maria Kruse Hansen, Linu M. John, Annette Plesner, Gao Sun, Morten Schlein, Rikke Bjerring Skyggebjerg, Thomas Kruse","doi":"10.1021/acs.jmedchem.4c02359","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02359","url":null,"abstract":"<i>Correction</i>: The following paragraph previously on page 11691 is now the footnote for Table 12 on page 11693. “Data are mean ± SEM measured as percent food intake relative to vehicle in rats after a single sc injection of 30 nmol/kg of the test substance. Data for cagrilintide have been published previously<sup>7</sup> giving rise to 85% and 84% reduction of food intake in the periods from 0–24 h and 24–48 h, respectively. SEM is the standard error of the mean.” <i>Correction:</i> The following paragraph was previously included as the footnotes for Table 9 on page 11692 and has been moved to page 11691. “From the in vitro data (Tables 10 and 11), it was apparent that selectivity was achieved for several peptides (<b>10</b>, <b>14</b>, <b>15</b>, <b>16</b>, <b>17</b>, <b>18</b>, <b>20</b>, and <b>21</b>). From the ThT assay (Table 9 and Supporting Information), only three of the AMYR selective peptides (<b>14</b>, <b>16</b>, and <b>21</b>) were able to resist physical stress for more than 40 h. Two peptides (<b>15</b> and <b>21</b>) had a selectivity ratio above 30. Peptide 6 and peptides <b>11</b>–<b>21</b> with neutral/high pI were chosen for further evaluation in vivo to evaluate their ability to reduce food intake in rats after a single administration and to have increased insights into the duration of effects from the peptides in vivo (Table 11).” This article has not yet been cited by other publications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"30 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816205","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}
Treating methicillin-resistant Staphylococcus aureus (MRSA) infection remains one of the most difficult challenges in clinical practice, primarily due to the resistance of MRSA to multiple antibiotics. Therefore, there is an urgent need to develop novel antibiotics with high efficacy and low cross-resistance rates. In this study, a series of novel pleuromutilin derivatives with coumarin structures were synthesized and subsequently assessed for their biological activities. Most of these derivatives showed potent antimicrobial activity against drug-resistant Gram-positive bacterial strains. Compound 14b displayed particularly rapid bactericidal effects, slow resistance development, and low cytotoxicity. Moreover, it decreased bacterial loads in the lung, liver, kidney, spleen, and heart and exhibited better antibacterial efficacy (ED50 = 11.16 mg/kg) than tiamulin (ED50 = 28.93 mg/kg) in a mouse model of systemic MRSA infection. Both in vitro and in vivo analyses suggest that compound 14b is a promising agent for the treatment of MRSA infections.
{"title":"Discovery of Novel Coumarin Pleuromutilin Derivatives as Potent Anti-MRSA Agents.","authors":"Kai Liu, Jing Xia, Yun Li, Bing-Bing Li, Meng-Qian Wang, Qian Zhou, Meng-Lin Ma, Qiu-Rong He, Wei-Qing Yang, Dong-Fang Liu, Zhou-Yu Wang, Ling-Ling Yang, Yuan-Yuan Zhang","doi":"10.1021/acs.jmedchem.4c01678","DOIUrl":"10.1021/acs.jmedchem.4c01678","url":null,"abstract":"<p><p>Treating methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) infection remains one of the most difficult challenges in clinical practice, primarily due to the resistance of MRSA to multiple antibiotics. Therefore, there is an urgent need to develop novel antibiotics with high efficacy and low cross-resistance rates. In this study, a series of novel pleuromutilin derivatives with coumarin structures were synthesized and subsequently assessed for their biological activities. Most of these derivatives showed potent antimicrobial activity against drug-resistant Gram-positive bacterial strains. Compound <b>14b</b> displayed particularly rapid bactericidal effects, slow resistance development, and low cytotoxicity. Moreover, it decreased bacterial loads in the lung, liver, kidney, spleen, and heart and exhibited better antibacterial efficacy (ED<sub>50</sub> = 11.16 mg/kg) than tiamulin (ED<sub>50</sub> = 28.93 mg/kg) in a mouse model of systemic MRSA infection. Both in vitro and in vivo analyses suggest that compound <b>14b</b> is a promising agent for the treatment of MRSA infections.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"21030-21048"},"PeriodicalIF":6.8,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737781","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 : 2024-12-12DOI: 10.1021/acs.jmedchem.4c02878
Campbell McInnes
FLT3-ITD (internal tandem duplication) is a key driver of acute myeloid leukemia (AML), and several FDA-approved drugs target this mutant kinase. This Viewpoint describes the discovery of inhibitors targeting point mutants and the development of SILA123, a highly potent and selective type II FLT3 inhibitor. In in vivo studies, SILA-123 significantly suppressed tumor growth in allograft models, demonstrating its potential in treating resistant AML.
{"title":"Overcoming Resistance to FLT3-ITD Therapeutics","authors":"Campbell McInnes","doi":"10.1021/acs.jmedchem.4c02878","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02878","url":null,"abstract":"FLT3-ITD (internal tandem duplication) is a key driver of acute myeloid leukemia (AML), and several FDA-approved drugs target this mutant kinase. This Viewpoint describes the discovery of inhibitors targeting point mutants and the development of SILA123, a highly potent and selective type II FLT3 inhibitor. In <i>in vivo</i> studies, SILA-123 significantly suppressed tumor growth in allograft models, demonstrating its potential in treating resistant AML.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"233 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816207","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 : 2024-12-11DOI: 10.1021/acs.jmedchem.4c01306
Manal Shamsi, Waddhaah M. Al-Asbahy, Hakim Q. N. Al-Areqi, Fahad A. M. Alzowahi
The ligands 2,2′-bipyridyl and indole-3-carboxylic acid were used to create a Sn(IV) complex, which was then synthesized and carefully characterized using elemental analysis and spectroscopic techniques (UV–vis, IR, 1H, 13C, and 119Sn NMR, and ESI-MS) and RXPD. Utilizing biophysical techniques such as UV–vis, fluorescence titrations, circular dichroism, FTIR (for HSA), and cleavage activity (for DNA), in vitro binding studies of Sn(IV) complex and DNA/HSA were satisfied with the strong electrostatic binding interaction of the Sn(IV) complex via the phosphate backbone of the DNA helix as well as in the subdomain IIA of HSA. The observed trend in the binding interactions and computational studies of the Sn(IV) complex was attributed to the nature of the ligands bound to the Sn(IV) center that influences their in vitro activities. The Sn(IV) complex showed sufficient effectiveness to be considered a viable candidate for the creation of anticancer medications.
{"title":"Probing the Biomolecular Interactions of DNA/HSA with the New Sn(IV) Complex and Computational Perspectives: Design, Synthesis, Characterization, Anticancer Activity, and Molecular Modeling Approach","authors":"Manal Shamsi, Waddhaah M. Al-Asbahy, Hakim Q. N. Al-Areqi, Fahad A. M. Alzowahi","doi":"10.1021/acs.jmedchem.4c01306","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01306","url":null,"abstract":"The ligands 2,2′-bipyridyl and indole-3-carboxylic acid were used to create a Sn(IV) complex, which was then synthesized and carefully characterized using elemental analysis and spectroscopic techniques (UV–vis, IR, <sup>1</sup>H, <sup>13</sup>C, and <sup>119</sup>Sn NMR, and ESI-MS) and RXPD. Utilizing biophysical techniques such as UV–vis, fluorescence titrations, circular dichroism, FTIR (for HSA), and cleavage activity (for DNA), <i>in vitro</i> binding studies of Sn(IV) complex and DNA/HSA were satisfied with the strong electrostatic binding interaction of the Sn(IV) complex <i>via</i> the phosphate backbone of the DNA helix as well as in the subdomain IIA of HSA. The observed trend in the binding interactions and computational studies of the Sn(IV) complex was attributed to the nature of the ligands bound to the Sn(IV) center that influences their <i>in vitro</i> activities. The Sn(IV) complex showed sufficient effectiveness to be considered a viable candidate for the creation of anticancer medications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"2 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142810033","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}
Amino-berberine has remained underexplored due to limited biological evaluation and total synthesis approaches. In inflammation therapy, soluble Epoxide Hydrolase (sEH) is a promising target, yet natural scaffolds remain underutilized. Our study advances the field by redesigning natural compounds─berberine and sanguinarine─with strategic urea modifications and hydrogenated frameworks, creating novel sEH inhibitors with enhanced in vivo efficacy. Through total synthesis and structure–activity relationship studies of amino-berberine derivatives, chiral tetrahydroberberine (R)-14i (coded LXZ-42) emerged as the most potent lead, with an IC50 value of 1.20 nM. (R)-14i showed reduced CYP enzyme impact, potent therapeutic effects on acute pancreatitis, no acute in vivo toxicity, and superior pharmacokinetic properties, with an oral bioavailability of 89.3%. Structural insights from crystallography of (R)-14i bound to sEH revealed key interactions: three with the tetrahydroberberine framework and three hydrogen bonds with the urea group, highlighting (R)-14i as a novel lead for sEH-targeted therapies in inflammation.
{"title":"Redesigning Berberines and Sanguinarines to Target Soluble Epoxide Hydrolase for Enhanced Anti-Inflammatory Efficacy","authors":"Xing-Zhou Liu, Xiao-Yu Du, Wei-Song Xie, Jing Ding, Min-Zhen Zhu, Zi-Qiang Feng, Hao Wang, Yue Feng, Ming-Jia Yu, Si-Meng Liu, Wen-Tian Liu, Xin-Hong Zhu, Jian-Hua Liang","doi":"10.1021/acs.jmedchem.4c02202","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02202","url":null,"abstract":"Amino-berberine has remained underexplored due to limited biological evaluation and total synthesis approaches. In inflammation therapy, soluble Epoxide Hydrolase (sEH) is a promising target, yet natural scaffolds remain underutilized. Our study advances the field by redesigning natural compounds─berberine and sanguinarine─with strategic urea modifications and hydrogenated frameworks, creating novel sEH inhibitors with enhanced <i>in vivo</i> efficacy. Through total synthesis and structure–activity relationship studies of amino-berberine derivatives, chiral tetrahydroberberine <b>(<i>R</i>)-14i</b> (coded <b>LXZ-42</b>) emerged as the most potent lead, with an IC<sub>50</sub> value of 1.20 nM. <b>(<i>R</i>)-14i</b> showed reduced CYP enzyme impact, potent therapeutic effects on acute pancreatitis, no acute <i>in vivo</i> toxicity, and superior pharmacokinetic properties, with an oral bioavailability of 89.3%. Structural insights from crystallography of <b>(<i>R</i>)-14i</b> bound to sEH revealed key interactions: three with the tetrahydroberberine framework and three hydrogen bonds with the urea group, highlighting <b>(<i>R</i>)-14i</b> as a novel lead for sEH-targeted therapies in inflammation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"132 41 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805138","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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