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Pharmacological effects of small molecule BCR-ABL tyrosine kinase inhibitors on platelet function.
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2024-11-22 DOI: 10.1124/jpet.124.002104
Yiheng Zhang, Chih-Jen Yang, Alexander R Melrose, Jiaqing Pang, Kirrali Schofield, Serena D Song, Iván Parra-Izquierdo, Tony J Zheng, Joseph P Lyssikatos, Stefan D Gross, Joseph J Shatzel, Owen J T McCarty, Joseph E Aslan

Tyrosine kinase inhibitors (TKIs) targeting the breakpoint cluster region-ABL fusion protein, such as imatinib (Gleevec), have revolutionized targeted cancer therapies. However, drug resistance and side effects, particularly those affecting hemostasis, continue to pose significant challenges for TKI therapies. As tyrosine kinases serve pivotal roles in platelet hemostatic function, we investigated the potential impact of both established and emerging ABL TKIs on human platelet activities ex vivo. Our study included standard-of-care agents (eg, imatinib and nilotinib) and second-generation ABL inhibitors, including ponatinib and bosutinib, designed to mitigate drug resistance. Additionally, we explored the effects of allosteric inhibitors targeting the myristoyl pocket of ABL (eg, asciminib and GNF-2) and novel agents in preclinical development, including ELVN-919, which uniquely exhibits high specificity for the ABL kinase active site. Our findings reveal that while ABL inhibitors such as ponatinib and bosutinib impede platelet activity, highly specific new-generation ABL inhibitors, including first-in-class therapeutics, do not impact platelet function ex vivo. Overall, these new insights around the effects of ABL TKIs on platelet function could inform the development of targeted therapies with reduced hematologic toxicities. SIGNIFICANCE STATEMENT: This study examines the effects of clinically relevant small molecule breakpoint cluster region (BCR)-ABL tyrosine kinase inhibitors (TKIs) on platelet activity. This analysis includes first-time assessments of agents such as asciminib and ELVN-919 on human platelet function ex vivo, alongside established therapies (eg, imatinib, ponatinib) with well characterized effects on platelet function, to discern potential antiplatelet and other effects of BCR-ABL TKIs and inform clinical safety.

{"title":"Pharmacological effects of small molecule BCR-ABL tyrosine kinase inhibitors on platelet function.","authors":"Yiheng Zhang, Chih-Jen Yang, Alexander R Melrose, Jiaqing Pang, Kirrali Schofield, Serena D Song, Iván Parra-Izquierdo, Tony J Zheng, Joseph P Lyssikatos, Stefan D Gross, Joseph J Shatzel, Owen J T McCarty, Joseph E Aslan","doi":"10.1124/jpet.124.002104","DOIUrl":"https://doi.org/10.1124/jpet.124.002104","url":null,"abstract":"<p><p>Tyrosine kinase inhibitors (TKIs) targeting the breakpoint cluster region-ABL fusion protein, such as imatinib (Gleevec), have revolutionized targeted cancer therapies. However, drug resistance and side effects, particularly those affecting hemostasis, continue to pose significant challenges for TKI therapies. As tyrosine kinases serve pivotal roles in platelet hemostatic function, we investigated the potential impact of both established and emerging ABL TKIs on human platelet activities ex vivo. Our study included standard-of-care agents (eg, imatinib and nilotinib) and second-generation ABL inhibitors, including ponatinib and bosutinib, designed to mitigate drug resistance. Additionally, we explored the effects of allosteric inhibitors targeting the myristoyl pocket of ABL (eg, asciminib and GNF-2) and novel agents in preclinical development, including ELVN-919, which uniquely exhibits high specificity for the ABL kinase active site. Our findings reveal that while ABL inhibitors such as ponatinib and bosutinib impede platelet activity, highly specific new-generation ABL inhibitors, including first-in-class therapeutics, do not impact platelet function ex vivo. Overall, these new insights around the effects of ABL TKIs on platelet function could inform the development of targeted therapies with reduced hematologic toxicities. SIGNIFICANCE STATEMENT: This study examines the effects of clinically relevant small molecule breakpoint cluster region (BCR)-ABL tyrosine kinase inhibitors (TKIs) on platelet activity. This analysis includes first-time assessments of agents such as asciminib and ELVN-919 on human platelet function ex vivo, alongside established therapies (eg, imatinib, ponatinib) with well characterized effects on platelet function, to discern potential antiplatelet and other effects of BCR-ABL TKIs and inform clinical safety.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100020"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Evaluation of systemic and brain pharmacokinetic parameters for repurposing metformin using intravenous bolus administration.
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2024-11-22 DOI: 10.1124/jpet.124.002152
Sejal Sharma, Yong Zhang, Dhavalkumar Patel, Khondker Ayesha Akter, Sounak Bagchi, Ali Ehsan Sifat, Ehsan Nozohouri, Yeseul Ahn, Vardan T Karamyan, Ulrich Bickel, Thomas J Abbruscato

Metformin's potential in treating ischemic stroke and neurodegenerative conditions is of growing interest. Yet, the absence of established systemic and brain pharmacokinetic (PK) parameters at relevant preclinical doses presents a significant knowledge gap. This study highlights these PK parameters and the importance of using pharmacologically relevant preclinical doses to study pharmacodynamics in stroke and related neurodegenerative diseases. A liquid chromatography with tandem mass spectrometry method to measure metformin levels in plasma, brain, and cerebrospinal fluid was developed and validated. In vitro assays examined brain tissue binding and metabolic stability. Intravenous bolus administration of metformin to C57BL6 mice covered a low- to high-dose range maintaining pharmacological relevance. Quantification of metformin in the brain was used to assess brain PK parameters, such as unidirectional blood-to-brain constant (Kin) and unbound brain-to-plasma ratio (Kp, uu, brain). Metformin exhibited no binding in the mouse plasma and brain and remained metabolically stable. It rapidly entered the brain, reaching detectable levels in as little as 5 minutes. A Kin value of 1.87 ± 0.27 μL/g/min was obtained. As the dose increased, Kp, uu, brain showed decreased value, implying saturation, but this did not affect an increase in absolute brain concentrations. Metformin was quantifiable in the cerebrospinal fluid at 30 minutes but decreased over time, with concentrations lower than those in the brain across all doses. Our findings emphasize the importance of metformin dose selection based on PK parameters for preclinical pharmacological studies. We anticipate further investigations focusing on PKs and pharmacodynamics in disease conditions, such as stroke. SIGNIFICANCE STATEMENT: The study establishes crucial pharmacokinetic parameters of metformin for treating ischemic stroke and neurodegenerative diseases, addressing a significant knowledge gap. It further emphasizes the importance of selecting pharmacologically relevant preclinical doses. The findings highlight metformin's rapid brain entry, minimal binding, and metabolic stability. The necessity of considering pharmacokinetic parameters in preclinical studies provides a foundation for future investigations into metformin's efficacy for neurodegenerative disease(s).

{"title":"Evaluation of systemic and brain pharmacokinetic parameters for repurposing metformin using intravenous bolus administration.","authors":"Sejal Sharma, Yong Zhang, Dhavalkumar Patel, Khondker Ayesha Akter, Sounak Bagchi, Ali Ehsan Sifat, Ehsan Nozohouri, Yeseul Ahn, Vardan T Karamyan, Ulrich Bickel, Thomas J Abbruscato","doi":"10.1124/jpet.124.002152","DOIUrl":"https://doi.org/10.1124/jpet.124.002152","url":null,"abstract":"<p><p>Metformin's potential in treating ischemic stroke and neurodegenerative conditions is of growing interest. Yet, the absence of established systemic and brain pharmacokinetic (PK) parameters at relevant preclinical doses presents a significant knowledge gap. This study highlights these PK parameters and the importance of using pharmacologically relevant preclinical doses to study pharmacodynamics in stroke and related neurodegenerative diseases. A liquid chromatography with tandem mass spectrometry method to measure metformin levels in plasma, brain, and cerebrospinal fluid was developed and validated. In vitro assays examined brain tissue binding and metabolic stability. Intravenous bolus administration of metformin to C57BL6 mice covered a low- to high-dose range maintaining pharmacological relevance. Quantification of metformin in the brain was used to assess brain PK parameters, such as unidirectional blood-to-brain constant (K<sub>in</sub>) and unbound brain-to-plasma ratio (K<sub>p, uu, brain</sub>). Metformin exhibited no binding in the mouse plasma and brain and remained metabolically stable. It rapidly entered the brain, reaching detectable levels in as little as 5 minutes. A K<sub>in</sub> value of 1.87 ± 0.27 μL/g/min was obtained. As the dose increased, K<sub>p, uu, brain</sub> showed decreased value, implying saturation, but this did not affect an increase in absolute brain concentrations. Metformin was quantifiable in the cerebrospinal fluid at 30 minutes but decreased over time, with concentrations lower than those in the brain across all doses. Our findings emphasize the importance of metformin dose selection based on PK parameters for preclinical pharmacological studies. We anticipate further investigations focusing on PKs and pharmacodynamics in disease conditions, such as stroke. SIGNIFICANCE STATEMENT: The study establishes crucial pharmacokinetic parameters of metformin for treating ischemic stroke and neurodegenerative diseases, addressing a significant knowledge gap. It further emphasizes the importance of selecting pharmacologically relevant preclinical doses. The findings highlight metformin's rapid brain entry, minimal binding, and metabolic stability. The necessity of considering pharmacokinetic parameters in preclinical studies provides a foundation for future investigations into metformin's efficacy for neurodegenerative disease(s).</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100013"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
VERU-111, an orally available tubulin inhibitor, suppresses ovarian tumor growth and metastasis.
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2024-11-22 DOI: 10.1124/jpet.124.002298
Shelby Waddell, Guannan Zhao, Ziping Liu, Hao Chen, Wenjing Zhang, Yaohong Wang, Duane D Miller, Junming Yue, Wei Li

Ovarian cancer is the most lethal gynecological malignancy, with a 5-year survival rate of approximately 50%. The dismal prognosis is due in part to metastatic disease and acquired drug resistance to conventional chemotherapies such as taxanes. Colchicine binding site inhibitors (CBSIs) are attractive alternatives to taxanes because they could potentially achieve oral bioavailability and overcome drug resistance associated with the prolonged use of taxanes. VERU-111 is one of the most advanced CBSIs that is orally available, potent, and well tolerated and has shown good efficacy in several preclinical solid tumor models. Here, we demonstrate for the first time the in vitro potency of VERU-111 as well as its efficacy at inhibiting tumor growth and metastasis in an orthotopic ovarian cancer mouse model. VERU-111 has nanomolar potency against ovarian cancer cell lines and strongly inhibits colony formation, proliferation, invasion, and migration. VERU-111 disrupts microtubule formation to induce mitotic catastrophe and ultimately apoptosis in a concentration-dependent manner. The efficacy of VERU-111 was comparable with standard chemotherapy paclitaxel, the current first-line treatment of ovarian cancer, with no observed synergy with combination paclitaxel + VERU-111 treatment. In vivo, VERU-111 markedly suppressed ovarian tumor growth and completely suppressed distant organ metastasis. Together, these results support VERU-111 for its potential as a novel therapy for ovarian cancer, particularly for late-stage metastatic disease. SIGNIFICANCE STATEMENT: VERU-111 is an investigational new drug and has comparable efficacy as paclitaxel in suppressing tumor cell proliferation, colony formation, and migration in ovarian cancer models in vitro and has potent in vivo antitumor and antimetastatic activity in an orthotopic ovarian cancer mouse model. VERU-111 has low systemic toxicity and, unlike paclitaxel, is orally bioavailable and is not a substrate for the major drug efflux transporters, making it a promising and attractive alternative to taxane-based therapy.

{"title":"VERU-111, an orally available tubulin inhibitor, suppresses ovarian tumor growth and metastasis.","authors":"Shelby Waddell, Guannan Zhao, Ziping Liu, Hao Chen, Wenjing Zhang, Yaohong Wang, Duane D Miller, Junming Yue, Wei Li","doi":"10.1124/jpet.124.002298","DOIUrl":"https://doi.org/10.1124/jpet.124.002298","url":null,"abstract":"<p><p>Ovarian cancer is the most lethal gynecological malignancy, with a 5-year survival rate of approximately 50%. The dismal prognosis is due in part to metastatic disease and acquired drug resistance to conventional chemotherapies such as taxanes. Colchicine binding site inhibitors (CBSIs) are attractive alternatives to taxanes because they could potentially achieve oral bioavailability and overcome drug resistance associated with the prolonged use of taxanes. VERU-111 is one of the most advanced CBSIs that is orally available, potent, and well tolerated and has shown good efficacy in several preclinical solid tumor models. Here, we demonstrate for the first time the in vitro potency of VERU-111 as well as its efficacy at inhibiting tumor growth and metastasis in an orthotopic ovarian cancer mouse model. VERU-111 has nanomolar potency against ovarian cancer cell lines and strongly inhibits colony formation, proliferation, invasion, and migration. VERU-111 disrupts microtubule formation to induce mitotic catastrophe and ultimately apoptosis in a concentration-dependent manner. The efficacy of VERU-111 was comparable with standard chemotherapy paclitaxel, the current first-line treatment of ovarian cancer, with no observed synergy with combination paclitaxel + VERU-111 treatment. In vivo, VERU-111 markedly suppressed ovarian tumor growth and completely suppressed distant organ metastasis. Together, these results support VERU-111 for its potential as a novel therapy for ovarian cancer, particularly for late-stage metastatic disease. SIGNIFICANCE STATEMENT: VERU-111 is an investigational new drug and has comparable efficacy as paclitaxel in suppressing tumor cell proliferation, colony formation, and migration in ovarian cancer models in vitro and has potent in vivo antitumor and antimetastatic activity in an orthotopic ovarian cancer mouse model. VERU-111 has low systemic toxicity and, unlike paclitaxel, is orally bioavailable and is not a substrate for the major drug efflux transporters, making it a promising and attractive alternative to taxane-based therapy.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100006"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Zero-length crosslinking: A breakthrough approach for evaluating target engagement in α-synuclein immunotherapy.
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2024-12-27 DOI: 10.1016/j.jpet.2024.100036
Jean-Christophe Rochet, Wenzhu Qi, Deniz Kirik
{"title":"Zero-length crosslinking: A breakthrough approach for evaluating target engagement in α-synuclein immunotherapy.","authors":"Jean-Christophe Rochet, Wenzhu Qi, Deniz Kirik","doi":"10.1016/j.jpet.2024.100036","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100036","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100036"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Therapeutic targeting of full-length interleukin-33 protein levels with cell-permeable decoy peptides attenuates fibrosis in the bleomycin model in vivo.
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2024-11-22 DOI: 10.1124/jpet.123.002050
Sergei P Atamas, Virginia Lockatell, Nevins W Todd, John C Papadimitriou, Violeta Rus, Katerina N Lugkey, Stefanie N Vogel, Vladimir Y Toshchakov, Irina G Luzina

Interleukin (IL)-33 has been shown to centrally regulate, among other processes, inflammation and fibrosis. Both intracellular full-length (FLIL33) precursor and extracellular mature cytokine (MIL33) forms exert such regulation, albeit differentially. Drug development efforts to target the IL-33 pathway have focused mostly on MIL33 and its specific cell-surface receptor, ST2, with limited attempts to negotiate the pathophysiological contributions from FLIL33. Furthermore, even a successful strategy for targeting MIL33 effects would arguably benefit from a simultaneous attenuation of the levels of FLIL33, which remains the continuous source of MIL33 supply. We therefore sought to develop an approach to depleting FLIL33 protein levels. We previously reported that the steady-state levels of FLIL33 are controlled in part through its proteasomal degradation and that such regulation can be mapped to a segment in the N-terminal portion of FLIL33. We hypothesized that disruption of this regulation would lead to a decrease in FLIL33 levels, thus inducing a beneficial therapeutic effect in an IL-33-dependent pathology. To test this hypothesis, we designed and tested cell-permeable decoy peptides, which mimic the target N-terminal FLIL33 region. We argued that such mimic peptides would compete with FLIL33 for the components of the native FLIL33 production and maintenance molecular machinery. Administered in the therapeutic regimen to bleomycin-challenged mice, the tested cell-permeable decoy peptides alleviated the overall severity of the disease by restoring body weight loss and attenuating accumulation of collagen in the lungs. This proof-of-principle study lays the foundation for future work toward the development of this prospective therapeutic approach. SIGNIFICANCE STATEMENT: An antifibrotic therapeutic approach is proposed and preclinically tested in mice in vivo based on targeting the full-length IL-33 precursor protein. Peptide fusion constructs consisted of a cell-permeable sequence fused with a sequence mimicking an N-terminal segment of IL-33 precursor that is responsible for this protein's stability. Systemic administration of such peptides to mice in either the acute intratracheal or chronic systemic bleomycin challenge models leads to a decrease in the bleomycin-induced elevations of pulmonary IL-33 and collagen.

{"title":"Therapeutic targeting of full-length interleukin-33 protein levels with cell-permeable decoy peptides attenuates fibrosis in the bleomycin model in vivo.","authors":"Sergei P Atamas, Virginia Lockatell, Nevins W Todd, John C Papadimitriou, Violeta Rus, Katerina N Lugkey, Stefanie N Vogel, Vladimir Y Toshchakov, Irina G Luzina","doi":"10.1124/jpet.123.002050","DOIUrl":"https://doi.org/10.1124/jpet.123.002050","url":null,"abstract":"<p><p>Interleukin (IL)-33 has been shown to centrally regulate, among other processes, inflammation and fibrosis. Both intracellular full-length (FLIL33) precursor and extracellular mature cytokine (MIL33) forms exert such regulation, albeit differentially. Drug development efforts to target the IL-33 pathway have focused mostly on MIL33 and its specific cell-surface receptor, ST2, with limited attempts to negotiate the pathophysiological contributions from FLIL33. Furthermore, even a successful strategy for targeting MIL33 effects would arguably benefit from a simultaneous attenuation of the levels of FLIL33, which remains the continuous source of MIL33 supply. We therefore sought to develop an approach to depleting FLIL33 protein levels. We previously reported that the steady-state levels of FLIL33 are controlled in part through its proteasomal degradation and that such regulation can be mapped to a segment in the N-terminal portion of FLIL33. We hypothesized that disruption of this regulation would lead to a decrease in FLIL33 levels, thus inducing a beneficial therapeutic effect in an IL-33-dependent pathology. To test this hypothesis, we designed and tested cell-permeable decoy peptides, which mimic the target N-terminal FLIL33 region. We argued that such mimic peptides would compete with FLIL33 for the components of the native FLIL33 production and maintenance molecular machinery. Administered in the therapeutic regimen to bleomycin-challenged mice, the tested cell-permeable decoy peptides alleviated the overall severity of the disease by restoring body weight loss and attenuating accumulation of collagen in the lungs. This proof-of-principle study lays the foundation for future work toward the development of this prospective therapeutic approach. SIGNIFICANCE STATEMENT: An antifibrotic therapeutic approach is proposed and preclinically tested in mice in vivo based on targeting the full-length IL-33 precursor protein. Peptide fusion constructs consisted of a cell-permeable sequence fused with a sequence mimicking an N-terminal segment of IL-33 precursor that is responsible for this protein's stability. Systemic administration of such peptides to mice in either the acute intratracheal or chronic systemic bleomycin challenge models leads to a decrease in the bleomycin-induced elevations of pulmonary IL-33 and collagen.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100008"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Clinical development of the GluN2B-selective NMDA receptor inhibitor NP10679 for the treatment of neurologic deficit after subarachnoid hemorrhage.
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2024-11-26 DOI: 10.1124/jpet.124.002334
Haichen Wang, Raymond J Dingledine, Scott J Myers, Stephen F Traynelis, Chuan Fang, Yanli Tan, George W Koszalka, Daniel T Laskowitz

Aneurysmal subarachnoid hemorrhage (SAH) may be associated with cerebral vasospasm, which can lead to delayed cerebral ischemia, infarction, and worsened functional outcomes. The delayed nature of cerebral ischemia secondary to SAH-related vasculopathy presents a window of opportunity for the evaluation of well tolerated neuroprotective agents administered soon after ictus. Secondary ischemic injury in SAH is associated with increased extracellular glutamate, which can overactivate N-methyl-d-aspartate receptors (NMDARs), thereby triggering NMDAR-mediated cellular damage. In this study, we evaluated the effect of the pH-sensitive GluN2B-selective NMDAR inhibitor NP10679 on neurologic impairment after SAH. This compound demonstrates a selective increase in potency at the acidic extracellular pH levels that occur in the setting of ischemia. We found that NP10679 produced durable improvement of behavioral deficits in a well characterized murine model of SAH, and these effects were greater than those produced by nimodipine alone, the current standard of care. In addition, we observed an unexpected reduction in SAH-induced luminal narrowing of the middle cerebral artery. Neither nimodipine nor NP10679 alters each other's pharmacokinetic profile, suggesting no obvious drug-drug interactions. Based on allometric scaling of both toxicological and efficacy data, the therapeutic margin in humans should be at least 2. These results further demonstrate the utility of pH-dependent neuroprotective agents and GluN2B-selective NMDAR inhibitors as potential therapeutic strategies for the treatment of aneurysmal SAH. SIGNIFICANCE STATEMENT: This report describes the properties and utility of the GluN2B-selective pH-sensitive N-methyl-d-aspartate receptor inhibitor, NP10679, in a well characterized rodent model of subarachnoid hemorrhage. We show that the administration of NP10679 improves long-term neurological function following subarachnoid hemorrhage and that in rats, there are no drug-drug interactions between NP10679 and nimodipine, the standard of care for this indication.

{"title":"Clinical development of the GluN2B-selective NMDA receptor inhibitor NP10679 for the treatment of neurologic deficit after subarachnoid hemorrhage.","authors":"Haichen Wang, Raymond J Dingledine, Scott J Myers, Stephen F Traynelis, Chuan Fang, Yanli Tan, George W Koszalka, Daniel T Laskowitz","doi":"10.1124/jpet.124.002334","DOIUrl":"https://doi.org/10.1124/jpet.124.002334","url":null,"abstract":"<p><p>Aneurysmal subarachnoid hemorrhage (SAH) may be associated with cerebral vasospasm, which can lead to delayed cerebral ischemia, infarction, and worsened functional outcomes. The delayed nature of cerebral ischemia secondary to SAH-related vasculopathy presents a window of opportunity for the evaluation of well tolerated neuroprotective agents administered soon after ictus. Secondary ischemic injury in SAH is associated with increased extracellular glutamate, which can overactivate N-methyl-d-aspartate receptors (NMDARs), thereby triggering NMDAR-mediated cellular damage. In this study, we evaluated the effect of the pH-sensitive GluN2B-selective NMDAR inhibitor NP10679 on neurologic impairment after SAH. This compound demonstrates a selective increase in potency at the acidic extracellular pH levels that occur in the setting of ischemia. We found that NP10679 produced durable improvement of behavioral deficits in a well characterized murine model of SAH, and these effects were greater than those produced by nimodipine alone, the current standard of care. In addition, we observed an unexpected reduction in SAH-induced luminal narrowing of the middle cerebral artery. Neither nimodipine nor NP10679 alters each other's pharmacokinetic profile, suggesting no obvious drug-drug interactions. Based on allometric scaling of both toxicological and efficacy data, the therapeutic margin in humans should be at least 2. These results further demonstrate the utility of pH-dependent neuroprotective agents and GluN2B-selective NMDAR inhibitors as potential therapeutic strategies for the treatment of aneurysmal SAH. SIGNIFICANCE STATEMENT: This report describes the properties and utility of the GluN2B-selective pH-sensitive N-methyl-d-aspartate receptor inhibitor, NP10679, in a well characterized rodent model of subarachnoid hemorrhage. We show that the administration of NP10679 improves long-term neurological function following subarachnoid hemorrhage and that in rats, there are no drug-drug interactions between NP10679 and nimodipine, the standard of care for this indication.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100046"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Evidence for cytoprotective autophagy in response to HER2-targeted monoclonal antibodies.
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2024-11-22 DOI: 10.1124/jpet.123.002048
Ahmed M Elshazly, Aya A Elzahed, David A Gewirtz

The advent of HER2-targeted monoclonal antibodies such as trastuzumab has significantly improved the clinical outcomes for patients with breast cancer overexpressing HER2 and, more recently, also for gastric cancers. However, the development of resistance, as is frequently the case for other antineoplastic modalities, constrains their clinical efficacy. Multiple molecular mechanisms and signaling pathways have been investigated for their potential involvement in the development of resistance to HER2-targeted therapies, among which is autophagy. Autophagy is an inherent cellular mechanism whereby cytoplasmic components are selectively degraded to maintain cellular homeostasis via the generation of energy and metabolic intermediates. Although the cytoprotective form of autophagy is thought to predominate, other forms of autophagy have also been identified in response to chemotherapeutic agents in various tumor models; these include cytotoxic, cytostatic, and nonprotective functional forms of autophagy. In this review, we provide an overview of the autophagic machinery induced in response to HER2-targeted monoclonal antibodies, with a focus on trastuzumab and trastuzumab-emtansine, in an effort to determine whether autophagy targeting or modulation could be translated clinically to increase their effectiveness and/or overcome the development of resistance. SIGNIFICANCE STATEMENT: This manuscript is one in a series of papers that interrogate the role(s) of the autophagy induced in response to antineoplastic agents in various cancer models. This series of papers was developed in an effort to establish whether autophagy targeting or modulation is likely to be an effective adjuvant strategy to increase the efficacy of cancer chemotherapeutic agents. This review explores the relationship between the autophagic machinery and HER2-targeted therapies.

{"title":"Evidence for cytoprotective autophagy in response to HER2-targeted monoclonal antibodies.","authors":"Ahmed M Elshazly, Aya A Elzahed, David A Gewirtz","doi":"10.1124/jpet.123.002048","DOIUrl":"https://doi.org/10.1124/jpet.123.002048","url":null,"abstract":"<p><p>The advent of HER2-targeted monoclonal antibodies such as trastuzumab has significantly improved the clinical outcomes for patients with breast cancer overexpressing HER2 and, more recently, also for gastric cancers. However, the development of resistance, as is frequently the case for other antineoplastic modalities, constrains their clinical efficacy. Multiple molecular mechanisms and signaling pathways have been investigated for their potential involvement in the development of resistance to HER2-targeted therapies, among which is autophagy. Autophagy is an inherent cellular mechanism whereby cytoplasmic components are selectively degraded to maintain cellular homeostasis via the generation of energy and metabolic intermediates. Although the cytoprotective form of autophagy is thought to predominate, other forms of autophagy have also been identified in response to chemotherapeutic agents in various tumor models; these include cytotoxic, cytostatic, and nonprotective functional forms of autophagy. In this review, we provide an overview of the autophagic machinery induced in response to HER2-targeted monoclonal antibodies, with a focus on trastuzumab and trastuzumab-emtansine, in an effort to determine whether autophagy targeting or modulation could be translated clinically to increase their effectiveness and/or overcome the development of resistance. SIGNIFICANCE STATEMENT: This manuscript is one in a series of papers that interrogate the role(s) of the autophagy induced in response to antineoplastic agents in various cancer models. This series of papers was developed in an effort to establish whether autophagy targeting or modulation is likely to be an effective adjuvant strategy to increase the efficacy of cancer chemotherapeutic agents. This review explores the relationship between the autophagic machinery and HER2-targeted therapies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100007"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Quantification of cinpanemab (BIIB054) binding to α-synuclein in cerebrospinal fluid of phase 1 single ascending dose samples.
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2024-11-22 DOI: 10.1124/jpet.124.002199
YuTing Liu, Minhua Yang, Kyle Fraser, Danielle Graham, Paul H Weinreb, Andreas Weihofen, Warren D Hirst, Jesse M Cedarbaum, Blake Pepinsky

Through its pathological and genetic association with Parkinson disease (PD), α-synuclein (α-syn) remains a favorable therapeutic target that is being investigated using various modalities, including many passive immunotherapy approaches clinically targeting different forms of α-syn and epitopes. Although published studies from some immunotherapy trials have demonstrated engagement in plasma, none has shown direct drug-antigen interactions in the disease-relevant compartment, the central nervous system. Cinpanemab (BIIB054) selectively targets pathological aggregated α-syn with low-affinity binding to monomeric forms. The avidity-driven binding, low drug concentration, and the very low α-syn levels, plus its heterogeneous nature in cerebrospinal fluid (CSF), made it impossible to measure drug-target interactions by conventional assays. Here we overcame these challenges by using zero-length crosslinking to stabilize the BIIB054-α-syn complexes and then quantified the crosslinked complexes using a Meso Scale Discovery electrochemiluminescence assay. CSF samples from healthy volunteers (HVs, n = 46) and individuals with PD (PD, n = 18) from study 228HV101 (phase 1 clinical trial of BIIB054) demonstrated dose- and time-dependent binding of cinpanemab to α-syn with measurable complexes detected at doses ≥15 mg/kg. Complex formation displayed a direct positive correlation to drug concentration (Spearman rank correlation = 0.8295 [HV], 0.8032 [PD] P < .0001 [HV, PD]). The observed binding of cinpanemab to α-syn in CSF is consistent with its low intrinsic affinity for α-syn monomer and provides evidence that the drug is behaving with expected binding dynamics in the central nervous system compartment. SIGNIFICANCE STATEMENT: A zero-length crosslinking method with Meso Scale Discovery detection was developed to enable quantification of cinpanemab-α-synuclein (α-syn) complexes in clinical cerebrospinal fluid samples by preventing signal loss caused by their rapid dissociation. Observed dose- and time-dependent binding was consistent with cinpanemab's affinity for α-syn and provided confidence the drug had engaged its target at the desired site of action. This is the first demonstration of α-syn binding by an antibody in clinical samples from the central nervous system.

{"title":"Quantification of cinpanemab (BIIB054) binding to α-synuclein in cerebrospinal fluid of phase 1 single ascending dose samples.","authors":"YuTing Liu, Minhua Yang, Kyle Fraser, Danielle Graham, Paul H Weinreb, Andreas Weihofen, Warren D Hirst, Jesse M Cedarbaum, Blake Pepinsky","doi":"10.1124/jpet.124.002199","DOIUrl":"https://doi.org/10.1124/jpet.124.002199","url":null,"abstract":"<p><p>Through its pathological and genetic association with Parkinson disease (PD), α-synuclein (α-syn) remains a favorable therapeutic target that is being investigated using various modalities, including many passive immunotherapy approaches clinically targeting different forms of α-syn and epitopes. Although published studies from some immunotherapy trials have demonstrated engagement in plasma, none has shown direct drug-antigen interactions in the disease-relevant compartment, the central nervous system. Cinpanemab (BIIB054) selectively targets pathological aggregated α-syn with low-affinity binding to monomeric forms. The avidity-driven binding, low drug concentration, and the very low α-syn levels, plus its heterogeneous nature in cerebrospinal fluid (CSF), made it impossible to measure drug-target interactions by conventional assays. Here we overcame these challenges by using zero-length crosslinking to stabilize the BIIB054-α-syn complexes and then quantified the crosslinked complexes using a Meso Scale Discovery electrochemiluminescence assay. CSF samples from healthy volunteers (HVs, n = 46) and individuals with PD (PD, n = 18) from study 228HV101 (phase 1 clinical trial of BIIB054) demonstrated dose- and time-dependent binding of cinpanemab to α-syn with measurable complexes detected at doses ≥15 mg/kg. Complex formation displayed a direct positive correlation to drug concentration (Spearman rank correlation = 0.8295 [HV], 0.8032 [PD] P < .0001 [HV, PD]). The observed binding of cinpanemab to α-syn in CSF is consistent with its low intrinsic affinity for α-syn monomer and provides evidence that the drug is behaving with expected binding dynamics in the central nervous system compartment. SIGNIFICANCE STATEMENT: A zero-length crosslinking method with Meso Scale Discovery detection was developed to enable quantification of cinpanemab-α-synuclein (α-syn) complexes in clinical cerebrospinal fluid samples by preventing signal loss caused by their rapid dissociation. Observed dose- and time-dependent binding was consistent with cinpanemab's affinity for α-syn and provided confidence the drug had engaged its target at the desired site of action. This is the first demonstration of α-syn binding by an antibody in clinical samples from the central nervous system.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100003"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Innovation through imitation: IL-33 decoys show promise in pulmonary fibrosis.
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2024-12-27 DOI: 10.1016/j.jpet.2024.100035
Maya E Kotas, Erin D Gordon
{"title":"Innovation through imitation: IL-33 decoys show promise in pulmonary fibrosis.","authors":"Maya E Kotas, Erin D Gordon","doi":"10.1016/j.jpet.2024.100035","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100035","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100035"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Metformin in overcoming enzalutamide resistance in castration-resistant prostate cancer.
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-01-01 Epub Date: 2024-11-22 DOI: 10.1124/jpet.124.002424
Kendall Simpson, Derek B Allison, Daheng He, Jinpeng Liu, Chi Wang, Xiaoqi Liu

Androgen deprivation is the standard treatment for patients with prostate cancer. However, the disease eventually progresses as castration-resistant prostate cancer (CRPC). Enzalutamide, an androgen receptor inhibitor, is a typical drug for treating CRPC and with continuous reliance on the drug, can lead to enzalutamide resistance. This highlights the necessity for developing novel therapeutic targets to combat the gain of resistance. Metformin has been recently investigated for its potential antitumorigenic effects in many cancer types. In this study, we used enzalutamide and metformin in combination to explore the possible rescued efficacy of enzalutamide in the treatment of enzalutamide-resistant CRPC. We first tested the effects of this combination treatment on cell viability, drug synergy, and cell proliferation in enzalutamide-resistant CRPC cell lines. After combination treatment, we observed a decrease in cell proliferation and viability as well as a synergistic effect of both enzalutamide and metformin in vitro. Following these results, we sought to explore how combination treatment affected mitochondrial fitness using mitochondrial stress test analysis and mitochondrial membrane potential shifts due to metformin's action in inhibiting complex I of oxidative phosphorylation. We employed 2 different strategies for in vivo testing using 22Rv1 and LuCaP35CR xenograft models. Finally, RNA sequencing revealed a potential link in the downregulation of rat sarcoma-mitogen-activated protein kinase signaling following combination treatment. SIGNIFICANCE STATEMENT: Increasing evidence suggests that oxidative phosphorylation might play a critical role in the development of resistance to cancer therapy. This study showed that targeting oxidative phosphorylation with metformin can enhance the efficacy of enzalutamide in castration-resistant prostate cancer in vitro.

{"title":"Metformin in overcoming enzalutamide resistance in castration-resistant prostate cancer.","authors":"Kendall Simpson, Derek B Allison, Daheng He, Jinpeng Liu, Chi Wang, Xiaoqi Liu","doi":"10.1124/jpet.124.002424","DOIUrl":"https://doi.org/10.1124/jpet.124.002424","url":null,"abstract":"<p><p>Androgen deprivation is the standard treatment for patients with prostate cancer. However, the disease eventually progresses as castration-resistant prostate cancer (CRPC). Enzalutamide, an androgen receptor inhibitor, is a typical drug for treating CRPC and with continuous reliance on the drug, can lead to enzalutamide resistance. This highlights the necessity for developing novel therapeutic targets to combat the gain of resistance. Metformin has been recently investigated for its potential antitumorigenic effects in many cancer types. In this study, we used enzalutamide and metformin in combination to explore the possible rescued efficacy of enzalutamide in the treatment of enzalutamide-resistant CRPC. We first tested the effects of this combination treatment on cell viability, drug synergy, and cell proliferation in enzalutamide-resistant CRPC cell lines. After combination treatment, we observed a decrease in cell proliferation and viability as well as a synergistic effect of both enzalutamide and metformin in vitro. Following these results, we sought to explore how combination treatment affected mitochondrial fitness using mitochondrial stress test analysis and mitochondrial membrane potential shifts due to metformin's action in inhibiting complex I of oxidative phosphorylation. We employed 2 different strategies for in vivo testing using 22Rv1 and LuCaP35CR xenograft models. Finally, RNA sequencing revealed a potential link in the downregulation of rat sarcoma-mitogen-activated protein kinase signaling following combination treatment. SIGNIFICANCE STATEMENT: Increasing evidence suggests that oxidative phosphorylation might play a critical role in the development of resistance to cancer therapy. This study showed that targeting oxidative phosphorylation with metformin can enhance the efficacy of enzalutamide in castration-resistant prostate cancer in vitro.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 1","pages":"100034"},"PeriodicalIF":3.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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