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SLAS discovery : advancing life sciences R & D最新文献

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A novel high-throughput screening platform to identify inhibitors of DNAJB1-PRKACA-driven transcriptional activity in fibrolamellar carcinoma.
SLAS discovery : advancing life sciences R & D Pub Date : 2025-02-11 DOI: 10.1016/j.slasd.2025.100221
Nihal Bharath, Emma DiPietro, Olivia Durfee, Ina Kycia, Jen Splaine, Praveen Sethupathy, Michael Rogers, Khashayar Vakili
{"title":"A novel high-throughput screening platform to identify inhibitors of DNAJB1-PRKACA-driven transcriptional activity in fibrolamellar carcinoma.","authors":"Nihal Bharath, Emma DiPietro, Olivia Durfee, Ina Kycia, Jen Splaine, Praveen Sethupathy, Michael Rogers, Khashayar Vakili","doi":"10.1016/j.slasd.2025.100221","DOIUrl":"https://doi.org/10.1016/j.slasd.2025.100221","url":null,"abstract":"<p><p>Fibrolamellar carcinoma (FLC) is a primary liver cancer with a poor prognosis, primarily due to the lack of effective chemotherapeutic options. The DNAJB1-PRKACA (DP) gene fusion is recognized as the key oncogenic driver in FLC. This fusion arises from a ∼400 kb heterozygous deletion on chromosome 19, which fuses exon 1 of DNAJB1 with exons 2-10 of PRKACA, the gene encoding the catalytic subunit of protein kinase A (PKA). While targeting DP is considered a promising therapeutic approach, attempts to inhibit the kinase function of the DP fusion protein have been largely unsuccessful due to off-target effects on wild-type PKA. In response to this challenge, we developed a high-throughput screening (HTS) assay to identify inhibitors of DP's downstream signaling pathways involved in transcriptional regulation. Our previous research identified LINC00473 as a transcriptional marker for DP protein expression, and LINC00473 is known to be upregulated in FLC tumors. Additionally, evidence suggests that LINC00473 promotes FLC tumor growth. Based on the relationship between DP and LINC00473 expression, we engineered the HEK-DP-Luc reporter cell line by modifying HEK293 cells to express DP at the endogenous locus and to express the NanoLuc luciferase gene under the control of the LINC00473 promoter and enhancer. We have optimized the HEK-DP-Luc cells for HTS, and here we present our pipeline for primary screening and counter-screening to identify compounds that inhibit DP's downstream transcriptional activity. This HTS platform provides a novel approach for therapeutic drug discovery in FLC.</p>","PeriodicalId":74806,"journal":{"name":"SLAS discovery : advancing life sciences R & D","volume":" ","pages":"100221"},"PeriodicalIF":0.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416366","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}
引用次数: 0
A high-throughput response to the SARS-CoV-2 pandemic. 高通量应对 SARS-CoV-2 大流行。
SLAS discovery : advancing life sciences R & D Pub Date : 2024-05-16 DOI: 10.1016/j.slasd.2024.100160
Lynn Rasmussen, Shalisa Sanders, Melinda Sosa, Sara McKellip, N Miranda Nebane, Yohanka Martinez-Gzegozewska, Andrew Reece, Pedro Ruiz, Anna Manuvakhova, Ling Zhai, Brooke Warren, Aliyah Curry, Qinghua Zeng, J Robert Bostwick, Paige N Vinson
{"title":"A high-throughput response to the SARS-CoV-2 pandemic.","authors":"Lynn Rasmussen, Shalisa Sanders, Melinda Sosa, Sara McKellip, N Miranda Nebane, Yohanka Martinez-Gzegozewska, Andrew Reece, Pedro Ruiz, Anna Manuvakhova, Ling Zhai, Brooke Warren, Aliyah Curry, Qinghua Zeng, J Robert Bostwick, Paige N Vinson","doi":"10.1016/j.slasd.2024.100160","DOIUrl":"10.1016/j.slasd.2024.100160","url":null,"abstract":"<p><p>Four years after the beginning of the COVID-19 pandemic, it is important to reflect on the events that have occurred during that time and the knowledge that has been gained. The response to the pandemic was rapid and highly resourced; it was also built upon a foundation of decades of federally funded basic and applied research. Laboratories in government, pharmaceutical, academic, and non-profit institutions all played roles in advancing pre-2020 discoveries to produce clinical treatments. This perspective provides a summary of how the development of high-throughput screening methods in a biosafety level 3 (BSL-3) environment at Southern Research Institute (SR) contributed to pandemic response efforts. The challenges encountered are described, including those of a technical nature as well as those of working under the pressures of an unpredictable virus and pandemic.</p>","PeriodicalId":74806,"journal":{"name":"SLAS discovery : advancing life sciences R & D","volume":" ","pages":"100160"},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140961194","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}
引用次数: 0
Optimising cell-based bioassays via integrated design of experiments (ixDoE) - A practical guide. 通过综合实验设计(ixDoE)优化基于细胞的生物测定-实用指南。
SLAS discovery : advancing life sciences R & D Pub Date : 2022-10-01 DOI: 10.2139/ssrn.4107411
J. Solzin, K. Eppler, B. Knapp, H. Buchner, E. Bluhmki
{"title":"Optimising cell-based bioassays via integrated design of experiments (ixDoE) - A practical guide.","authors":"J. Solzin, K. Eppler, B. Knapp, H. Buchner, E. Bluhmki","doi":"10.2139/ssrn.4107411","DOIUrl":"https://doi.org/10.2139/ssrn.4107411","url":null,"abstract":"For process optimisation Design of Experiments (DoE) has long been established as a more powerful strategy than a One Factor at a Time approach. Nevertheless, DoE is not widely used especially in the field of cell-based bioassay development although it is known that complex interactions often exist. We believe that biopharmaceutical manufacturers are reluctant to move beyond standard practices due to the perceived costs, efforts, and complexity. We therefore introduce the integrated DoE (ixDoE) approach to target a smarter use of DoEs in the bioassay setting, specifically in optimising resources and time. Where in a standard practice 3 to 4 separate DoEs would be performed, our ixDoE approach includes the necessary statistical inference from only a single experimental set. Hence, we advocate for an innovative, ixDoE approach accompanied by a suitable statistical analysis strategy and present this as a practical guide for a typical bioassay development from basic research to biopharmaceutical industry.","PeriodicalId":74806,"journal":{"name":"SLAS discovery : advancing life sciences R & D","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85648679","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}
引用次数: 2
Kaposi's sarcoma-associated herpes virus-derived microRNA K12-1 over-activates the PI3K/Akt pathway to facilitate cancer progression in HIV-related gastrointestinal Kaposi's sarcoma. 卡波西氏肉瘤相关疱疹病毒衍生的microRNA K12-1过度激活PI3K/Akt通路，促进hiv相关胃肠道卡波西氏肉瘤的癌症进展。
SLAS discovery : advancing life sciences R & D Pub Date : 2022-04-01 DOI: 10.1016/j.slasd.2022.04.001
X. Huang, W. Rao, Chun Wang, Jiajie Lu, Ziqiong Li, Wenjie Kong, Yan Feng, T. Xu, Rziya Rziya, F. Gao
{"title":"Kaposi's sarcoma-associated herpes virus-derived microRNA K12-1 over-activates the PI3K/Akt pathway to facilitate cancer progression in HIV-related gastrointestinal Kaposi's sarcoma.","authors":"X. Huang, W. Rao, Chun Wang, Jiajie Lu, Ziqiong Li, Wenjie Kong, Yan Feng, T. Xu, Rziya Rziya, F. Gao","doi":"10.1016/j.slasd.2022.04.001","DOIUrl":"https://doi.org/10.1016/j.slasd.2022.04.001","url":null,"abstract":"","PeriodicalId":74806,"journal":{"name":"SLAS discovery : advancing life sciences R & D","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87956671","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}
引用次数: 2
Development of a High-Throughput Assay to Identify Inhibitors of the Ubiquitin-Conjugating Enzyme UBCH10. 一种高通量测定方法鉴定泛素偶联酶UBCH10抑制剂。
SLAS discovery : advancing life sciences R & D Pub Date : 2022-03-01 DOI: 10.1016/j.slasd.2022.03.007
P. Cléroux, L. Voisin, S. Meloche
{"title":"Development of a High-Throughput Assay to Identify Inhibitors of the Ubiquitin-Conjugating Enzyme UBCH10.","authors":"P. Cléroux, L. Voisin, S. Meloche","doi":"10.1016/j.slasd.2022.03.007","DOIUrl":"https://doi.org/10.1016/j.slasd.2022.03.007","url":null,"abstract":"","PeriodicalId":74806,"journal":{"name":"SLAS discovery : advancing life sciences R & D","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79049590","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}
引用次数: 2
Profiling oncogenic KRAS mutant drugs with a cell-based Lumit p-ERK immunoassay. 基于细胞的Lumit p-ERK免疫分析分析致癌KRAS突变药物。
SLAS discovery : advancing life sciences R & D Pub Date : 2022-03-01 DOI: 10.1016/j.slasd.2022.03.001
Matthew R Swiatnicki, Laurie Engel, Riva Shrestha, Juliano Alves, S. Goueli, H. Zegzouti
{"title":"Profiling oncogenic KRAS mutant drugs with a cell-based Lumit p-ERK immunoassay.","authors":"Matthew R Swiatnicki, Laurie Engel, Riva Shrestha, Juliano Alves, S. Goueli, H. Zegzouti","doi":"10.1016/j.slasd.2022.03.001","DOIUrl":"https://doi.org/10.1016/j.slasd.2022.03.001","url":null,"abstract":"","PeriodicalId":74806,"journal":{"name":"SLAS discovery : advancing life sciences R & D","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85785046","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}
引用次数: 1
Three-Dimensional Cell Cultures in Drug Discovery and Development. 药物发现与开发中的三维细胞培养。
SLAS discovery : advancing life sciences R & D Pub Date : 2017-01-01 DOI: 10.1177/2472555217696795
Ye Fang, R. Eglen
{"title":"Three-Dimensional Cell Cultures in Drug Discovery and Development.","authors":"Ye Fang, R. Eglen","doi":"10.1177/2472555217696795","DOIUrl":"https://doi.org/10.1177/2472555217696795","url":null,"abstract":"The past decades have witnessed significant efforts toward the development of three-dimensional (3D) cell cultures as systems that better mimic in vivo physiology. Today, 3D cell cultures are emerging, not only as a new tool in early drug discovery but also as potential therapeutics to treat disease. In this review, we assess leading 3D cell culture technologies and their impact on drug discovery, including spheroids, organoids, scaffolds, hydrogels, organs-on-chips, and 3D bioprinting. We also discuss the implementation of these technologies in compound identification, screening, and development, ranging from disease modeling to assessment of efficacy and safety profiles.","PeriodicalId":74806,"journal":{"name":"SLAS discovery : advancing life sciences R & D","volume":"1984 1","pages":"2472555217696795"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82228766","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}
引用次数: 266
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