ASPET discovery最新文献

{"title":"Insights and perspectives into the etiology of TKI-induced cardiotoxicity.","authors":"Vivian Xu, Bagdad Ahmed, Brent Boleslav, Donald E Mager, Alex Sparreboom, Jason A Sprowl, Kevin M Huang","doi":"10.1016/j.aspetd.2026.100025","DOIUrl":"10.1016/j.aspetd.2026.100025","url":null,"abstract":"<p><p>Tyrosine kinase inhibitors (TKIs) are a class of drugs that have significantly improved survival outcomes and revolutionized the treatment landscape for cancer patients. This is due to their ability to suppress the dysregulation of phosphorylation targets contributing to tumor progression; however, many TKIs approved to treat cancer are associated with adverse cardiac events, including potentially lethal cardiotoxicity. Despite extensive research on kinase signaling pathways, the mechanisms that regulate the movement of TKIs across cardiac cell membranes to interfere with the targets associated with TKI-induced cardiotoxicity remain to be fully elucidated. In this review, we focus on (1) summarizing the purported intracellular signaling pathways associated with TKI-induced cardiotoxicity, (2) the interaction of TKIs with membrane transporters, and (3) recent technological and methodological advances that can be leveraged to study the role of membrane transporters in the etiology of TKI-induced cardiotoxicity.</p><p><strong>Significance statement: </strong>Tyrosine kinase inhibitors (TKIs) have transformed cancer treatment but are increasingly recognized for causing cardiotoxicity. Defining the interplay between TKIs and membrane transporters will improve our mechanistic understanding of cardiotoxicity, particularly how intracellular drug disposition may critically influence susceptibility to essential cardiac kinase targets. Improving our understanding of this mechanism will aid in refining cardiac safety assessments of TKIs and enable transporter-informed strategies to mitigate cardiac risk while maintaining anticancer efficacy.</p>","PeriodicalId":520505,"journal":{"name":"ASPET discovery","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13410921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148623736","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":"Differential effects of acute versus repeated chemogenetic activation of the mesocorticolimbic dopamine pathway on cocaine choice in male and female TH:Cre rats.","authors":"Hannah L Robinson, Matthew L Banks","doi":"10.1016/j.aspetd.2026.100020","DOIUrl":"10.1016/j.aspetd.2026.100020","url":null,"abstract":"<p><strong>Rationale: </strong>Mesocorticolimbic dopamine neurotransmission is hypothesized to play a central role in both cocaine reinforcement and amphetamine maintenance-induced decreases in cocaine self-administration. One method to selectively modulate dopamine neurotransmission is by using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Therefore, the study goal was to selectively activate ventral tegmental area (VTA) dopaminergic neurons using DREADDs and determine the effects of acute and repeated activation of these neurons on cocaine self-administration using a cocaine-vs-food choice procedure in female and male rats.</p><p><strong>Methods: </strong>Two main experiments were conducted in tyrosine hydroxylase (TH):Cre female and male rats trained to respond under a concurrent \"choice\" schedule of IV cocaine and liquid food availability during daily behavioral sessions. Experiment 1 determined acute deschloroclozapine (DCZ) effects before and after VTA Gq-DREADD expression. Experiment 2 determined repeated DCZ effects via osmotic pump both pre and post Gq-DREADD expression.</p><p><strong>Results: </strong>Cocaine maintained a dose-dependent increase in cocaine choice pre- and post-VTA DREADD expression. Acute and continuous DCZ in the absence of DREADD expression did not alter cocaine choice. Acute DCZ significantly increased cocaine choice in rats expressing Gq-DREADDs similar to acute amphetamine. Continuous DCZ treatment via osmotic pump post Gq-DREADD expression failed to significantly alter cocaine choice.</p><p><strong>Conclusions: </strong>These results suggest acute activation of mesocorticolimbic VTA neurons is sufficient to enhance cocaine's relative reinforcing effectiveness. The lack of effect following continuous DCZ suggests potential tolerance to DCZ effects complicating the utility of these tools in rigorous behavioral neuroscience research.</p>","PeriodicalId":520505,"journal":{"name":"ASPET discovery","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13102296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147794905","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":"Emerging concepts on one-carbon metabolism as a unique and actionable vulnerability in cancer.","authors":"Mathew Schneider, Zhanjun Hou, Larry H Matherly","doi":"10.1016/j.aspetd.2026.100029","DOIUrl":"https://doi.org/10.1016/j.aspetd.2026.100029","url":null,"abstract":"<p><p>Metabolic reprogramming is a defining feature of cancer, and folate-mediated one-carbon (C1) metabolism occupies a central role in supporting malignant growth, survival, and immune evasion. Although cytosolic C1 enzymes have long been exploited for the therapy of a host of cancers through the use of \"classical\" antifolates, growing evidence suggests that mitochondrial C1 metabolism is a critical driver of tumor progression, metastasis, and redox homeostasis. Mitochondrial serine catabolism via serine hydroxymethyltransferase 2 and 5,10-methylene tetrahydrofolate dehydrogenase 2 provides formate, glycine, and reducing equivalents to sustain nucleotide and amino acid biosynthesis, biological methylation reactions, and antioxidant defenses. Dysregulation of mitochondrial C1 metabolism promotes \"formate overflow\", alters tumor-immune interactions, and supports metastatic signaling. This review synthesizes recent key advances in folate biology, and compartmentalized C1 metabolism, leading to the development of an exciting new generation of cytosolic- and mitochondrial-targeted therapies. We examine emerging links between C1 metabolism and the tumor microenvironment, including relationships between C1 metabolism and immune suppression, T cell infiltration, and macrophage polarization. Finally, we highlight critical unresolved questions and vexing future challenges in implementing the next generation of C1-targeted anticancer agents. Collectively, these insights underscore the remarkable biology of C1 metabolism, and mitochondrial C1 metabolism in paticular, and its potential as a multifaceted and therapeutically actionable vulnerability in cancer.</p><p><strong>Significance statement: </strong>This minireview summarizes recent advances in folate biology and one-carbon (C1) metabolism. Topical areas include mechanisms of membrane transport, compartmentalization of C1 metabolism and its role in tumor biology, and the relationship between C1 biology and the tumor microenvironment. The goal of this study is to provide an evolving framework for discovery of tumor-specific vulnerabilities in C1 metabolism that can be exploited for therapy.</p>","PeriodicalId":520505,"journal":{"name":"ASPET discovery","volume":"2 ","pages":"100029"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13690414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149280569","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":"NEK2 inhibition alleviates lipopolysaccharide-induced endothelial injury.","authors":"Saikat Fakir, Md Matiur Rahman Sarker, Madan Sigdel, Nektarios Barabutis","doi":"10.1016/j.aspetd.2025.100002","DOIUrl":"10.1016/j.aspetd.2025.100002","url":null,"abstract":"<p><p>The endothelial barrier regulates substance transfer across an extensive surface area, and vascular leakage may contribute to various inflammatory conditions, including acute respiratory distress syndrome and sepsis. NEK2 possesses a significant role in regulating cellular processes, and its overexpression has been linked to human disease. The present study investigates the effects of NEK2 inhibitor NCL 00017509 in endothelial barrier dysfunction and inflammation. Our results indicate that the aforementioned compound effectively suppresses lipopolysaccharide-induced activation of Cofilin and MLC2, which are crucial cytoskeletal components. NEK2 inhibition reduced endothelial paracellular permeability, reactive oxygen species generation, and phosphorylation of key inflammatory proteins (eg, ERK1/2, P38, STAT1, and STAT3) in cells exposed to lipopolysaccharide. Further investigation into the application of NEK2 inhibitors in preclinical models of direct and indirect lung injury will substantiate our findings.</p>","PeriodicalId":520505,"journal":{"name":"ASPET discovery","volume":"1 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12009629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056998","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":"Evaluation of molecular glue-induced neomorphic protein-protein interaction with a cell lysate-based time-resolved fluorescence resonance energy transfer assay.","authors":"Xiulei Mo, Yuhong Du, Haian Fu","doi":"10.1016/j.aspetd.2025.100003","DOIUrl":"10.1016/j.aspetd.2025.100003","url":null,"abstract":"<p><p>Neo-protein-protein interactions (neoPPI) induced by mutated amino acid residues present a promising class of therapeutic targets for proximity pharmacology-enabled drug discovery. Small molecule compounds, such as cyclosporin and FK506, have the capability to mimic the mutational effect to create new interaction interfaces to enhance the interaction of a protein with an unrelated, or low affinity protein. Such small molecules can function as molecular glues to purposefully generate neoPPIs for physiological reprogramming and therapeutic intervention. Thus, an unbiased approach for the systematic discovery of neoPPI-inducing compounds is much needed to accelerate the proximity pharmacology field. With the demonstrated small molecule induced neoPPI of oncogenic KRAS with cyclophilin A (CYPA), here we report the development of a robust cell lysate-based time-resolved fluorescence resonance energy transfer (TR-FRET) assay to characterize KRAS-CYPA neoPPI inducing molecular glues. We show that the developed TR-FRET assay can monitor the induced interaction of CYPA with oncogenic KRAS variants, KRAS-G12C, G12D and G12V. The assay was optimized to achieve a robust performance in a miniaturized format, which was utilized to demonstrate the potent effect of RMC-7977, a known molecular glue, in inducing the KRAS-CYPA interaction. This validated assay platform allows for the characterization of molecular glue-induced KRAS-CYPA neoPPI, which is readily applicable to explore the vast chemical space for the discovery of novel KRAS-CYPA neoPPI inducers and can be generally applicable for unbiased discovery of proximity-inducing molecular glues.</p>","PeriodicalId":520505,"journal":{"name":"ASPET discovery","volume":"1 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13035376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147597464","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":"Targeting ribonucleotide reductase to enhance the antileukemic activity of gilteritinib against chemoresistant <i>FLT3</i>- internal tandem duplication acute myeloid leukemia.","authors":"Nibal Eid, Jianlei Zhao, Jenna Thibodeau, Holly Edwards, Jing Li, Xun Bao, Lisa Polin, Juiwanna Kushner, Sijana H Dzinic, Kathryn White, Steven A Buck, Jessica B Back, Paul M Stemmer, Maurgan Lee, Seongho Kim, Jeffrey W Taub, Yubin Ge","doi":"10.1016/j.aspetd.2025.100014","DOIUrl":"10.1016/j.aspetd.2025.100014","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) cases harboring <i>FMS-like tyrosine kinase 3</i> (<i>FLT3</i>) internal tandem duplication (<i>FLT3</i>-ITD) mutations have poor clinical outcomes. Gilteritinib is a United States Food and Drug Administration-approved FLT3 inhibitor for treating relapsed/refractory (R/R) <i>FLT3</i>-mutated AML; however, monotherapy shows short-lived responses, highlighting the need for combination therapies. Increased ribonucleotide reductase regulatory subunit M2 (RRM2) was detected in cytarabine-resistant (AraC-R) <i>FLT3</i>-ITD AML cell lines and patient-derived xenograft (PDX) cells, accompanied by increased dNDPs determined by proteomics, western blotting, and metabolomics studies. shRNA knockdown of <i>RRM2</i> significantly enhanced cell death induced by the ribonucleotide reductase inhibitor, hydroxyurea (HU). Treatment of MV4-11/AraC-R and the PDX cells with variable concentrations of gilteritinib (25-1000 nM) almost completely abolished RRM2 in the cells even at the lowest concentration and was accompanied by a plateau of cell death. Pretreatment with HU (12.5-500 <i>μ</i>M) for 48 hours followed by gilteritinib (25-100 nM) for another 24 hours had a strong synergistic effect on the AraC-R <i>FLT3</i>-ITD AML cell lines and the PDX cells. Increasing gilteritinib concentrations by 10-fold did not result in further increased cell death. HU treatment induced RRM2 which was abolished by gilteritinib treatment, whereas gilteritinib treatment induced FLT3 which was canceled by HU, demonstrating reciprocal overcoming of drug resistance. Given that both drugs are Food and Drug Administration approved, and HU is well tolerated in both pediatric and adult populations as well as being cost-effective, establishing in vivo models could pave the path to clinical trials, ultimately providing a bridge to transplantation for R/R <i>FLT3</i>-ITD AML while minimizing toxicity.</p>","PeriodicalId":520505,"journal":{"name":"ASPET discovery","volume":"1 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13344374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148414550","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":"Strain-dependent neuronal disposition and toxicity of paclitaxel in mice.","authors":"Thomas Drabison, Yue Xu, Eman A Ahmed, Jack C Stromatt, Nathan Colasanti, Shruthi Kandalai, Kevin M Huang, Alex Sparreboom, Shuiying Hu, Leah M Pyter, Eric D Eisenmann","doi":"10.1016/j.aspetd.2025.100005","DOIUrl":"10.1016/j.aspetd.2025.100005","url":null,"abstract":"<p><p>Paclitaxel is an antineoplastic agent that is associated with debilitating adverse effects, especially paclitaxel-induced peripheral neuropathy (PIPN). Although preclinical models have been used to characterize the mechanisms underlying PIPN, experimental differences in these models, including the dose, route, schedule of the drug, and the species and strain of the animals used, limit our ability to compare and interpret results. Furthermore, uncertainties persist regarding potential dependence of paclitaxel disposition and toxicity on the route of administration or genetic background of the animal model. In this study, we address this gap by systematically investigating the relationship among route- and strain-specific pharmacokinetic profiles, organ accumulation, and the associated toxicity phenotypes in preclinical models of PIPN. Using a panel of 7 commonly used mouse strains, we observed that the plasma pharmacokinetics of paclitaxel are strain dependent. Using 2 representative strains (C57Bl/6 and CD2F1), longitudinal studies show similar results for distribution of paclitaxel in the dorsal root ganglia (DRG) within the peripheral nervous system, with a 2-fold magnitude of difference. Ensuing studies indicated that the accumulation of paclitaxel in the DRG is correlated with susceptibility to mechanical allodynia, a key marker of PIPN. Our study implies that DRG accumulation, rather than plasma exposure, contributes to the development of PIPN, and this understanding is expected to inform the further development of translationally relevant models and effective therapeutic strategies for managing PIPN.</p><p><strong>Significance statement: </strong>This investigation compares paclitaxel pharmacokinetics using 7 strains of mice and 2 routes of administration and longitudinally explores pharmacodynamics using 2 representative strains, which informs cross-study comparisons and the validation of translationally relevant model systems. These findings support the notion that accumulation within dorsal root ganglia, rather than plasma exposure, is correlated with the development of peripheral neuropathy. This insight is anticipated to guide the future development of effective therapeutic strategies for managing paclitaxel-induced peripheral neuropathy.</p>","PeriodicalId":520505,"journal":{"name":"ASPET discovery","volume":"1 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13290288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148321579","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}