ACS Pharmacology and Translational Science最新文献

{"title":"Suite of Biochemical and Cell-Based Assays for the Characterization of Kirsten Rat Sarcoma (KRAS) Inhibitors and Degraders","authors":"Medhanie Kidane,&nbsp;Rene M. Hoffman,&nbsp;Jennifer K. Wolfe-Demarco,&nbsp;Ting-Yu Huang,&nbsp;Chi-Ling Teng,&nbsp;Saheli Samanta,&nbsp;Luis M. Gonzalez Lira,&nbsp;Jennifer Lin-Jones,&nbsp;Gabriel Pallares,&nbsp;Jane E. Lamerdin,&nbsp;Nicole B. Servant,&nbsp;Chun-Yao Lee,&nbsp;Chao-Tsung Yang* and Jean A. Bernatchez*,&nbsp;","doi":"10.1021/acsptsci.4c0045010.1021/acsptsci.4c00450","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00450https://doi.org/10.1021/acsptsci.4c00450","url":null,"abstract":"<p >KRAS is an important oncogenic driver which is mutated in numerous cancers. Recent advances in the selective targeting of KRAS mutants via small molecule inhibitors and targeted protein degraders have generated an increase in research activity in this area in recent years. As such, there is a need for new assay platforms to profile next generation inhibitors which improve on the potency and selectivity of existing drug candidates, while evading the emergence of resistance. Here, we describe the development of a new panel of biochemical and cell-based assays to evaluate the binding and function of known chemical entities targeting mutant KRAS. Our assay panels generated selectivity profiles and quantitative binding interaction dissociation constants for small molecules and degraders against wild type, G12C, G12D, and G12V KRAS, which were congruent with published data. These assays can be leveraged for additional mutants of interest beyond those described in this study, using both overexpressed cell-free systems and cell-based systems with endogenous protein levels.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"3921–3934 3921–3934"},"PeriodicalIF":4.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00450","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suite of Biochemical and Cell-Based Assays for the Characterization of Kirsten Rat Sarcoma (KRAS) Inhibitors and Degraders.","authors":"Medhanie Kidane, Rene M Hoffman, Jennifer K Wolfe-Demarco, Ting-Yu Huang, Chi-Ling Teng, Saheli Samanta, Luis M Gonzalez Lira, Jennifer Lin-Jones, Gabriel Pallares, Jane E Lamerdin, Nicole B Servant, Chun-Yao Lee, Chao-Tsung Yang, Jean A Bernatchez","doi":"10.1021/acsptsci.4c00450","DOIUrl":"10.1021/acsptsci.4c00450","url":null,"abstract":"<p><p>KRAS is an important oncogenic driver which is mutated in numerous cancers. Recent advances in the selective targeting of KRAS mutants via small molecule inhibitors and targeted protein degraders have generated an increase in research activity in this area in recent years. As such, there is a need for new assay platforms to profile next generation inhibitors which improve on the potency and selectivity of existing drug candidates, while evading the emergence of resistance. Here, we describe the development of a new panel of biochemical and cell-based assays to evaluate the binding and function of known chemical entities targeting mutant KRAS. Our assay panels generated selectivity profiles and quantitative binding interaction dissociation constants for small molecules and degraders against wild type, G12C, G12D, and G12V KRAS, which were congruent with published data. These assays can be leveraged for additional mutants of interest beyond those described in this study, using both overexpressed cell-free systems and cell-based systems with endogenous protein levels.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"3921-3934"},"PeriodicalIF":4.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenging Reported Frizzled-Targeting Compounds in Selective Assays Reveals Lack of Functional Inhibition and Claimed Profiles","authors":"Alexey Koval*,&nbsp;Cédric Boudou and Vladimir L. Katanaev*,&nbsp;","doi":"10.1021/acsptsci.4c0057010.1021/acsptsci.4c00570","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00570https://doi.org/10.1021/acsptsci.4c00570","url":null,"abstract":"<p >Selective inhibitors of Frizzled (FZD) GPCRs are highly sought after as potentially highly efficacious and safe treatments for cancer as well as tools in regenerative medicine and fundamental science. In recent years, there have been several reports claiming the identification of small molecule agents that are selective toward certain FZD proteins using a variety of approaches. However, the majority of these studies lacked a selective functional assay to validate their functionality. In this study, we describe the development and application of a selective assay for individual FZD proteins. Our findings indicate that the majority of reported compounds lack the capacity to inhibit the functioning of the claimed FZD proteins when stimulated by a Wnt ligand in the canonical pathway. Instead, the compounds demonstrate a broad range of off-target effects, including inhibition of downstream pathway component(s) (3235-0367, SRI35959, carbamazepine, niclosamide), lack of activity (FzM1), and surprising antagonism of firefly luciferase (F7H). The only compound that fulfills the expected selectivity profile is peptide Fz7–21. These results highlight the necessity of implementing rigorous testing of the screening-derived compounds in selective functional assays and are important for the field of drug discovery and development targeting the highly demanded Wnt-FZD pathway.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"4144–4154 4144–4154"},"PeriodicalIF":4.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00570","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142850125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-Term Treatment with Fluoroethylnormemantine (FENM) Alleviated Memory Deficits, Amyloid Pathology, and Microglial Reaction in APP/PS1 Mice.","authors":"Aline Freyssin, Allison Carles, Barbara Moha, Gilles Rubinstenn, Tangui Maurice","doi":"10.1021/acsptsci.4c00522","DOIUrl":"10.1021/acsptsci.4c00522","url":null,"abstract":"<p><p>Fluoroethylnormemantine (FENM, RST-01) shows different pharmacological properties from Memantine. The drug is neuroprotective in pharmacological and transgenic mouse models of Alzheimer's disease (AD), particularly limiting the neuroinflammatory response to amyloid-β (Aβ) accumulation. In order to define early therapeutic intervention aimed at preventing AD and targeting the early activation of proinflammatory pathways, we examined the impact of chronic FENM treatment starting presymptomatically in APP_swe/PSEN1^∂E9 (APP/PS1) mice. APP/PS1 (32 males and 36 females) and wild-type (WT, 23 males and 36 females) mice received FENM (0, 1, and 5 mg/kg/day) in the drinking bottle between 3 and 12 months of age. They were tested once a month for spontaneous alternation and, at the end of the treatment, for object recognition, water-maze learning, and passive avoidance. Amyloid plaques, astrocytes, and microglia were assessed by immunofluorescence, and guanidine-soluble and insoluble Aβ_1-40/42 levels were determined in the hippocampal formation. Spontaneous alternation performances regularly decreased in APP/PS1, but not in WT mice. The FENM treatments (1 and 5 mg/kg) prevented the deficit. At 12 months of age, APP/PS1 treated with 1 mg/kg FENM showed significant improvements in all behavioral procedures tested. The astroglial reaction was not significantly attenuated by FENM in the <i>stratum radiatum</i>, <i>stratum moleculare,</i> and polymorph layer of the dentate gyrus. The microglial reaction was significantly decreased in the two latter areas. In the polymorph layer, a significant effect on amyloid plaques was measured. Global analyses of amyloid load showed attenuations of soluble and insoluble Aβ_1-40 levels and a significant decrease in the level of insoluble Aβ_1-42. Moreover, significant negative correlations were observed for FENM impacts on amyloid load or microglial activation and the alternation score. FENM confirmed, under a chronic presymptomatic treatment, its neuroprotective efficacy in AD. Our data particularly suggested that an impact on Aβ and microglia could be related to the preservation of cognitive functions.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"4069-4082"},"PeriodicalIF":4.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPARγ Functional Deficiency Expedited Fatty Acid Utilization in the Liver: A Foundation of Inflammatory Adipokine-Induced Hypolipemia in Rheumatoid Arthritis","authors":"Yan Wang,&nbsp;Yu-Qing Ruan,&nbsp;Lian-Jun He,&nbsp;Meng-Ke Song,&nbsp;Opeyemi Joshua Olatunji,&nbsp;Xiu Wang* and Jian Zuo*,&nbsp;","doi":"10.1021/acsptsci.4c0047010.1021/acsptsci.4c00470","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00470https://doi.org/10.1021/acsptsci.4c00470","url":null,"abstract":"<p >Triglyceride (TG) and its derivatives tend to be decreased in rheumatoid arthritis (RA) patients’ blood when inflammation progresses. Aside from the role as a lipid buffer, white adipose tissue (WAT) contributes to this abnormality via adipokines, which regulate many metabolic signals. This work investigated adipokine-caused hepatic changes and their involvement in RA-related hypolipemia. Given their immune similarities with RA and pathological representativeness, adjuvant-induced arthritis (AIA) rats and antigen-induced arthritis (AA) mice were adopted. Adipokine levels in the liver were quantified, and their hepatic conditions were assessed by oxidative/enzymatic indicators. Besides kit-based metabolite quantification, fatty acid levels in blood were accurately determined by GC–MS. Metabolic differences between healthy and AIA rats were further characterized by UPLC-MS². In vitro, preadipocytes were stimulated by RA/AIA blood serum or together with rosiglitazone, a PPARγ agonist. The medium was used to culture HepG2 cells. Some AIA rats were subjected to adipectomy or rosiglitazone therapies. Being WAT-released mediators, IL-1β, IL-6, MCP-1, adiponectin, and visfatin were apparently increased in AIA/AA rodent models’ liver, causing oxidative stress escalation, liver injuries, and fatty acid oxidation acceleration. This metabolic change was coincided to expression increase of CD36, FABP1, ATGL, and CPT-1A. PPARγ deficiency occurred both in vivo and in vitro under rheumatic conditions. RA serum reduced PPARγ expression and impaired its inhibition on NF-κB transcription activity in preadipocytes, which then led to excessive secretion of inflammatory adipokines. The corresponding medium down-regulated PPARγ and promoted expression of lipid catabolic enzymes in HepG2 cells. These effects were abrogated by rosiglitazone. Both the therapies impeded inflammatory secretion of WAT and fat catabolism of the liver. These data demonstrate that RA potentiates the capacity of WAT to secrete inflammatory adipokines. The resulting condition represses PPARγ expression and disrupts TG anabolism/catabolism balance in the liver. Because hepatocytes utilize more lipids but synthesize less, hypolipemia develops.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"3969–3983 3969–3983"},"PeriodicalIF":4.9,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPARγ Functional Deficiency Expedited Fatty Acid Utilization in the Liver: A Foundation of Inflammatory Adipokine-Induced Hypolipemia in Rheumatoid Arthritis.","authors":"Yan Wang, Yu-Qing Ruan, Lian-Jun He, Meng-Ke Song, Opeyemi Joshua Olatunji, Xiu Wang, Jian Zuo","doi":"10.1021/acsptsci.4c00470","DOIUrl":"10.1021/acsptsci.4c00470","url":null,"abstract":"<p><p>Triglyceride (TG) and its derivatives tend to be decreased in rheumatoid arthritis (RA) patients' blood when inflammation progresses. Aside from the role as a lipid buffer, white adipose tissue (WAT) contributes to this abnormality via adipokines, which regulate many metabolic signals. This work investigated adipokine-caused hepatic changes and their involvement in RA-related hypolipemia. Given their immune similarities with RA and pathological representativeness, adjuvant-induced arthritis (AIA) rats and antigen-induced arthritis (AA) mice were adopted. Adipokine levels in the liver were quantified, and their hepatic conditions were assessed by oxidative/enzymatic indicators. Besides kit-based metabolite quantification, fatty acid levels in blood were accurately determined by GC-MS. Metabolic differences between healthy and AIA rats were further characterized by UPLC-MS². In vitro, preadipocytes were stimulated by RA/AIA blood serum or together with rosiglitazone, a PPARγ agonist. The medium was used to culture HepG2 cells. Some AIA rats were subjected to adipectomy or rosiglitazone therapies. Being WAT-released mediators, IL-1β, IL-6, MCP-1, adiponectin, and visfatin were apparently increased in AIA/AA rodent models' liver, causing oxidative stress escalation, liver injuries, and fatty acid oxidation acceleration. This metabolic change was coincided to expression increase of CD36, FABP1, ATGL, and CPT-1A. PPARγ deficiency occurred both in vivo and in vitro under rheumatic conditions. RA serum reduced PPARγ expression and impaired its inhibition on NF-κB transcription activity in preadipocytes, which then led to excessive secretion of inflammatory adipokines. The corresponding medium down-regulated PPARγ and promoted expression of lipid catabolic enzymes in HepG2 cells. These effects were abrogated by rosiglitazone. Both the therapies impeded inflammatory secretion of WAT and fat catabolism of the liver. These data demonstrate that RA potentiates the capacity of WAT to secrete inflammatory adipokines. The resulting condition represses PPARγ expression and disrupts TG anabolism/catabolism balance in the liver. Because hepatocytes utilize more lipids but synthesize less, hypolipemia develops.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"3969-3983"},"PeriodicalIF":4.9,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperglycemia-Driven Insulin Signaling Defects Promote Parkinson’s Disease-like Pathology in Mice","authors":"Ritu Soni,&nbsp;Kirti Mathur,&nbsp;Hritik Rathod,&nbsp;Amit Khairnar and Jigna Shah*,&nbsp;","doi":"10.1021/acsptsci.4c0058610.1021/acsptsci.4c00586","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00586https://doi.org/10.1021/acsptsci.4c00586","url":null,"abstract":"<p >This study aims to determine the effect of chronic hyperglycemia, induced by a high-fat diet and STZ-induced diabetes, on the development of Parkinson’s disease-like characteristics. Understanding this relationship is crucial in pharmacology, neurology, and diabetes, as it could potentially lead to developing new therapeutic strategies for Parkinson’s disease. Our study employed a comprehensive approach to investigate the effect of hyperglycemia on Parkinson’s disease-like characteristics. Hyperglycemia was induced by a high-fat diet for 6- and 9-week duration with a single intraperitoneal STZ (100 mg/kg) injection at week 5 in C57/BL6 mice. Rotenone (10 mg/kg p.o.) was administered to C57/BL6 mice for 6 and 9 weeks. Time-dependent behavioral studies (wire-hang tests, pole tests, Y-maze tests, and round beam walk tests) were carried out to monitor pathology progression and deficits. Molecular protein levels (GLP1, PI3K, AKT, GSK-3β, NF-κB, and α-syn), oxidative stress (GSH and MDA) parameters, and histopathological alterations (H&amp;E and Nissl staining) were determined after 6 weeks as well as 9 weeks. After 9 weeks of study, molecular protein expression (p-AKT and p-α-syn) was determined. Hyperglycemia induced by HFD and STZ induced significant motor impairment in mice, correlated with the rotenone group. Insulin receptor signaling (GLP1/PI3K/AKT) was found to be disrupted in the HFD+STZ group and also in rotenone-treated mice, which further enhanced phosphorylation of α-syn, suggesting its role in α-syn accumulation. Histopathological alterations indicating neuroinflammation and neurodegeneration were quite evident in the HFD+STZ and rotenone groups. Exposure to hyperglycemia induced by HFD+STZ administration exhibits PD-like characteristics after 9 weeks of duration, which was correlative with rotenone-induced PD-like symptoms.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"4155–4164 4155–4164"},"PeriodicalIF":4.9,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperglycemia-Driven Insulin Signaling Defects Promote Parkinson's Disease-like Pathology in Mice.","authors":"Ritu Soni, Kirti Mathur, Hritik Rathod, Amit Khairnar, Jigna Shah","doi":"10.1021/acsptsci.4c00586","DOIUrl":"10.1021/acsptsci.4c00586","url":null,"abstract":"<p><p>This study aims to determine the effect of chronic hyperglycemia, induced by a high-fat diet and STZ-induced diabetes, on the development of Parkinson's disease-like characteristics. Understanding this relationship is crucial in pharmacology, neurology, and diabetes, as it could potentially lead to developing new therapeutic strategies for Parkinson's disease. Our study employed a comprehensive approach to investigate the effect of hyperglycemia on Parkinson's disease-like characteristics. Hyperglycemia was induced by a high-fat diet for 6- and 9-week duration with a single intraperitoneal STZ (100 mg/kg) injection at week 5 in C57/BL6 mice. Rotenone (10 mg/kg p.o.) was administered to C57/BL6 mice for 6 and 9 weeks. Time-dependent behavioral studies (wire-hang tests, pole tests, Y-maze tests, and round beam walk tests) were carried out to monitor pathology progression and deficits. Molecular protein levels (GLP1, PI3K, AKT, GSK-3β, NF-κB, and α-syn), oxidative stress (GSH and MDA) parameters, and histopathological alterations (H&E and Nissl staining) were determined after 6 weeks as well as 9 weeks. After 9 weeks of study, molecular protein expression (p-AKT and p-α-syn) was determined. Hyperglycemia induced by HFD and STZ induced significant motor impairment in mice, correlated with the rotenone group. Insulin receptor signaling (GLP1/PI3K/AKT) was found to be disrupted in the HFD+STZ group and also in rotenone-treated mice, which further enhanced phosphorylation of α-syn, suggesting its role in α-syn accumulation. Histopathological alterations indicating neuroinflammation and neurodegeneration were quite evident in the HFD+STZ and rotenone groups. Exposure to hyperglycemia induced by HFD+STZ administration exhibits PD-like characteristics after 9 weeks of duration, which was correlative with rotenone-induced PD-like symptoms.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"4155-4164"},"PeriodicalIF":4.9,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effective, but Safe? Physiologically Based Pharmacokinetic (PBPK)-Modeling-Based Dosing Study of Molnupiravir for Risk Assessment in Pediatric Subpopulations","authors":"Sarang Mishra,&nbsp; and ,&nbsp;Katharina Rox*,&nbsp;","doi":"10.1021/acsptsci.4c0053510.1021/acsptsci.4c00535","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00535https://doi.org/10.1021/acsptsci.4c00535","url":null,"abstract":"<p >Despite the end of COVID-19 pandemic, only intravenous remdesivir was approved for treatment of vulnerable pediatric populations. Molnupiravir is effective against viruses beyond SARS-CoV-2 and is orally administrable without CYP-interaction liabilities but has a burden of potential bone or cartilage toxicity, observed at doses exceeding 500 mg/kg/day in rats. Especially, activity of molnupiravir against viruses, such as Ebola, with high fatality rates and no treatment option warrants the exploration of potentially effective but safe doses for pediatric populations, i.e., neonates (0–27 days), infants (1–12 months), and children in early childhood (1–12 years). The bone and cartilage toxicity risk for these populations based on the preclinical results has not been systematically investigated yet. Using physiologically based pharmacokinetic (PBPK) modeling, we developed adult PBPK models for doses ranging from 50 to 1200 mg with minimal parameter optimization because of incorporation of CES1, a carboxylesterase. Therein, CES1 served as the main driver for conversion of molnupiravir to its active metabolite <i>β-d-N4</i>-hydroxycytidine (NHC). By incorporation of the ontogeny of CES1 for pediatric populations, we successfully developed PBPK models for different doses ranging from 10 to 75 mg/kg. For molnupiravir, efficacy is driven by the area under the curve (AUC). To achieve a similar AUC to that seen in adults, a dose of around 28 mg/kg BID was necessary in all three investigated pediatric subpopulations. This dose exceeded the safe dose observed in dogs and was slightly below the toxicity-associated human equivalent dose in rats. In summary, the pediatric PBPK models suggested that an efficacious dose posed a toxicity risk. These data confirmed the contraindication for children &lt;18 years.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"4112–4122 4112–4122"},"PeriodicalIF":4.9,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00535","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effective, but Safe? Physiologically Based Pharmacokinetic (PBPK)-Modeling-Based Dosing Study of Molnupiravir for Risk Assessment in Pediatric Subpopulations.","authors":"Sarang Mishra, Katharina Rox","doi":"10.1021/acsptsci.4c00535","DOIUrl":"10.1021/acsptsci.4c00535","url":null,"abstract":"<p><p>Despite the end of COVID-19 pandemic, only intravenous remdesivir was approved for treatment of vulnerable pediatric populations. Molnupiravir is effective against viruses beyond SARS-CoV-2 and is orally administrable without CYP-interaction liabilities but has a burden of potential bone or cartilage toxicity, observed at doses exceeding 500 mg/kg/day in rats. Especially, activity of molnupiravir against viruses, such as Ebola, with high fatality rates and no treatment option warrants the exploration of potentially effective but safe doses for pediatric populations, i.e., neonates (0-27 days), infants (1-12 months), and children in early childhood (1-12 years). The bone and cartilage toxicity risk for these populations based on the preclinical results has not been systematically investigated yet. Using physiologically based pharmacokinetic (PBPK) modeling, we developed adult PBPK models for doses ranging from 50 to 1200 mg with minimal parameter optimization because of incorporation of CES1, a carboxylesterase. Therein, CES1 served as the main driver for conversion of molnupiravir to its active metabolite <i>β-d-N4</i>-hydroxycytidine (NHC). By incorporation of the ontogeny of CES1 for pediatric populations, we successfully developed PBPK models for different doses ranging from 10 to 75 mg/kg. For molnupiravir, efficacy is driven by the area under the curve (AUC). To achieve a similar AUC to that seen in adults, a dose of around 28 mg/kg BID was necessary in all three investigated pediatric subpopulations. This dose exceeded the safe dose observed in dogs and was slightly below the toxicity-associated human equivalent dose in rats. In summary, the pediatric PBPK models suggested that an efficacious dose posed a toxicity risk. These data confirmed the contraindication for children <18 years.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"4112-4122"},"PeriodicalIF":4.9,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}