SLAS Discovery Volume 38 Features Research on Drug Discovery, Cellular Assays, and 3D Biology

SLAS Discovery Volume 38 Explores Drug Discovery Innovations and Advances in 3D Biology

Volume 38 of SLAS Discovery is now available, featuring a comprehensive review, three cutting-edge original research articles, and the editorial for its Special Issue, "Protocols in 3D Biology: Technologies and Methodologies Reshaping 3D Cell Culture." This edition delves into significant advancements spanning small molecule therapeutics to next-generation 3D cell culture technologies.

Featured Review

This review offers a detailed examination of the journey from large biological drugs to small molecule cytokine antagonists. Using TNFα and IL-17 as pivotal case studies, the article charts the evolution of therapeutic strategies. It further explores promising emerging modalities, including extracellular degraders and oral peptides, highlighting their potential as small molecule treatments for targets such as TSLP and TL1A.

The review "From Large to Small Cytokine Receptor Antagonists" details the evolution from biological drugs to small molecule cytokine antagonists, utilizing TNFα and IL-17 as key case studies.

Original Research Articles

A novel enzyme-linked immunosorbent assay (ELISA) platform is introduced for high-throughput screening of small molecule protein-protein interaction (PPI) inhibitors. This study successfully screened approximately 700 compounds, not only confirming the action of a known inhibitor but also identifying two new candidates: honokiol and zafirlukast. The platform demonstrates significant potential for accelerating drug discovery in this crucial area.

This new ELISA platform provides a high-throughput method for screening small molecule PPI inhibitors, leading to the discovery of novel compounds like honokiol and zafirlukast.

This article presents two significant innovations designed to enhance the cellular thermal shift assay (CETSA) for drug-target engagement studies. The first is an isothermal 1536-well uHTS platform, featuring controlled thermal ramp-up and luminescence detection, optimized for ultra-high throughput screening. The second innovation is a Gradient Peltier Device, which facilitates full melt curve analysis within a single plate. Both methods demonstrated a strong correlation with a fluorescence polarization assay when used to study the androgen receptor, underscoring their reliability and efficiency.

Two innovations for the cellular thermal shift assay (CETSA) — an isothermal 1536-well uHTS platform and a Gradient Peltier Device — promise to revolutionize ultra-high throughput screening.

MICRO-TAG, a fluorescence-based split-RNase S complementation method, offers a powerful new approach to directly quantify drug-target engagement within living cells across programmable temperature series. The effectiveness of this method was robustly demonstrated across key targets such as MAPK1, KRAS, and UBE2N. This technology provides a sensitive and scalable alternative, poised to accelerate early-stage drug discovery efforts by offering precise insights into drug-target interactions.

MICRO-TAG provides a sensitive and scalable fluorescence-based method for quantifying drug-target engagement directly in cells, making it a valuable tool for early-stage drug discovery.

Special Issue Editorial

The editorial for the Special Issue highlights the transformative impact of integrated technologies on 3D cell culture. It underscores how the synergy of bioprinting, bioreactors, automation, and AI-driven analysis is significantly advancing this field. The issue showcases diverse applications, ranging from patient-derived cancer organoids and skeletal muscle spheroids to intricate barrier-tissue models. This forward-looking perspective emphasizes a clear move towards integrated, high-throughput platforms that offer human-relevant alternatives to traditional preclinical models, thereby revolutionizing drug discovery and disease modeling.

The editorial for "Protocols in 3D Biology" emphasizes the integration of bioprinting, bioreactors, automation, and AI for creating high-throughput, human-relevant 3D cell culture models, reshaping preclinical research.