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

From Large to Small Cytokine Receptor Antagonists. 从大到小细胞因子受体拮抗剂。

IF 2.7

SLAS discovery : advancing life sciences R & D Pub Date : 2025-10-04 DOI: 10.1016/j.slasd.2025.100280

Pawel Leznicki, Karl Deacon, Bohdan Waszkowycz, John F Unitt

{"title":"From Large to Small Cytokine Receptor Antagonists.","authors":"Pawel Leznicki, Karl Deacon, Bohdan Waszkowycz, John F Unitt","doi":"10.1016/j.slasd.2025.100280","DOIUrl":"https://doi.org/10.1016/j.slasd.2025.100280","url":null,"abstract":"Here, we review general trends in biological and small molecule cytokine drug discovery, highlighting key learnings from two successful case studies (TNFα and IL-17), which have helped shape our understanding of how best to identify new small molecule cytokine antagonists. Over the past three decades, biological drugs have revolutionized the treatment of a wide range of diseases, from oncology to autoimmune diseases. Their ability to modulate extracellular targets, often inaccessible to conventional small molecule drugs due to their complex protein-protein interactions, has enabled the clinical validation of numerous novel cytokine targets. Despite their success, biological drugs have significant limitations. Challenges include poor oral bioavailability, tissue penetration and access to intracellular drug targets, as well as high manufacturing costs. These constraints have catalyzed efforts to develop small molecule equivalents that replicate the therapeutic efficacy of biologicals while overcoming their poor delivery and high production costs. Over the past twenty years, advances in structural biology, computational modeling, disease biology, hit-finding technologies, and medicinal chemistry have converged to collectively enable the identification and subsequent progression of small molecule cytokine modulators into clinical development. Looking ahead, we speculate on the future drug discovery landscape of this field with the likely emergence of small molecules drugs for a range of clinically validated cytokines like TSLP and TL1A. This evolution will be accelerated by the advent of novel modalities like extracellular degraders, oral peptide drugs and the development of next-generation biological drugs with multi-valency and improved delivery.","PeriodicalId":74806,"journal":{"name":"SLAS discovery : advancing life sciences R & D","volume":" ","pages":"100280"},"PeriodicalIF":2.7,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240333","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

The NLRP3 signaling pathway is a potential target for clinical translation in glioma treatment. NLRP3信号通路是胶质瘤治疗中临床翻译的潜在靶点。

IF 2.7

SLAS discovery : advancing life sciences R & D Pub Date : 2025-09-30 DOI: 10.1016/j.slasd.2025.100279

Fengyu Cheng, Yuanyuan Ming, Yunsong Pan, Tianpeng Zhang, Mingxing Li, Rui Zhang, Hui Zhou, Hui Shi

{"title":"The NLRP3 signaling pathway is a potential target for clinical translation in glioma treatment.","authors":"Fengyu Cheng, Yuanyuan Ming, Yunsong Pan, Tianpeng Zhang, Mingxing Li, Rui Zhang, Hui Zhou, Hui Shi","doi":"10.1016/j.slasd.2025.100279","DOIUrl":"https://doi.org/10.1016/j.slasd.2025.100279","url":null,"abstract":"Glioma, particularly glioblastoma (GBM), stands as the most prevalent and formidable tumor in neurosurgery, marked by relatively poor prognosis and high recurrence rates. Despite significant advancements in multimodal therapies-encompassing surgical intervention, radiotherapy, and systemic treatments such as chemotherapy and targeted agents-the overall survival rate for GBM still remains around 5%. In high-grade gliomas, dysregulated inflammatory pathways critically undermine the efficacy of surgical resection and subsequent targeted chemoradiotherapy, which are pivotal for managing these aggressive malignancies. Even with refined surgical techniques and chemotherapeutic mainstays like temozolomide (TMZ), patient prognoses persist in bleak territory, as survival rates languish far below clinical expectations. The NLRP3 inflammatory signaling pathway, extensively studied in this context, drives pathogenesis through allosteric activation and assembly into the NLRP3 inflammasome, catalyzing the maturation of IL-1β and IL-18, thereby triggering cascading inflammatory responses and pyroptosis. The NLRP3 signaling pathway plays a pivotal role in tumor progression and inflammatory responses, and targeted drugs have already entered Phase I clinical trials. Clinically, NLRP3 can serve as a prognostic biomarker, while the combined application of NLRP3-targeted drugs with novel materials and their technical specifics require further exploration. This review explores the NLRP3 pathway's mechanistic role in glioma progression, reviews cutting-edge clinical research on NLRP3-targeting therapeutics, and evaluates the transformative potential of modulating this pathway in glioma treatment-offering referential insights into its clinical implications and the inflammatory microenvironment's interplay with tumor dynamics.","PeriodicalId":74806,"journal":{"name":"SLAS discovery : advancing life sciences R & D","volume":" ","pages":"100279"},"PeriodicalIF":2.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214683","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

IF 2.7

SLAS discovery : advancing life sciences R & D Pub Date : 2025-09-01 Epub Date: 2025-08-05 DOI: 10.1016/j.slasd.2025.100256

Laura Calvo-Barreiro, Saurabh Upadhyay, Moustafa T Gabr

{"title":"Temperature-related intensity change (TRIC)-based high-throughput screening enables the discovery of small molecule CD28 binders.","authors":"Laura Calvo-Barreiro, Saurabh Upadhyay, Moustafa T Gabr","doi":"10.1016/j.slasd.2025.100256","DOIUrl":"10.1016/j.slasd.2025.100256","url":null,"abstract":"CD28 is a pivotal costimulatory receptor involved in T cell activation and immune regulation, positioning it as a key therapeutic target for inflammatory diseases, including inflammatory bowel disease (IBD). Despite its potential, small molecules targeting CD28 are still limited. To fill this gap, we developed a high-throughput screening (HTS) platform based on Temperature-Related Intensity Change (TRIC) technology, enabling rapid, immobilization-free screening of chemical libraries of small molecules. Using the Dianthus instrument, we applied our optimized TRIC assay for CD28 (signal-to-noise ratio of 21.99) to screen two MedChemExpress libraries: Small Molecule Immuno-Oncology Compounds (SMIOC) and Protein-Protein Interaction Inhibitors (PPII), identifying 50 initial hits. Following exclusion of compounds with dye interference or aggregation artifacts, 12 candidates were prioritized for further validation. Microscale thermophoresis (MST) confirmed dose-dependent binding of seven compounds to CD28, with affinities in the micromolar range. Surface plasmon resonance (SPR) further validated two compounds, EABP 02,303 and CTEP, as CD28 binders. These results demonstrate that our TRIC-based HTS platform is robust, scalable, and effective for identifying small molecule CD28 binders. The incorporation of orthogonal validation supports the reliability of our findings and highlights the feasibility of small-molecule discovery targeting CD28.","PeriodicalId":74806,"journal":{"name":"SLAS discovery : advancing life sciences R & D","volume":" ","pages":"100256"},"PeriodicalIF":2.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144801187","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 : 2024-07-01 Epub 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

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

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

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

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

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

引用次数: 266