<i>Assay Guidance Manual</i>: Quantitative Biology and Pharmacology in Preclinical Drug Discovery

Coussens, Nathan P.; Sittampalam, G. Sitta; Guha, Rajarshi; Brimacombe, Kyle R.; Grossman, A; Chung, Thomas D.Y.; Weidner, Jeffrey R.; Riss, Terry; Trask, O. Joseph; Auld, Douglas S.; Dahlin, Jayme L.; Devanaryan, Viswanath; Foley, Timothy L.; McGee, J; Kahl, Steven D.; Kales, Stephen C.; Arkin, Michelle R.; Baell, Jonathan B.; Bejcek, B; Gal-Edd, Neely; Glicksman, Marcie A.; Haas, Joseph V.; Iversen, Philip W.; Hoeppner, Marilu; Lathrop, Stacy; Sayers, Eric W; Liu, Hanguan; Trawick, Barton W.; McVey, Julie; Lemmon, Vance; Li, Zhuyin; McManus, Owen B.; Minor, Lisa; Napper, Andrew D.; Wildey, Mary Jo; Pacifici, Robert E.; Chin, William W.; Xia, Menghang; Xu, Xin; Lal‐Nag, Madhu; Hall, Matthew D.; Michael, Sam; Inglese, James; Simeonov, Anton; Austin, Christopher P.

doi:10.1111/cts.12570

Cited by 41 publications

(31 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3C ) showed that EC 50 values averaged 290 nM and 65% of values varied by no more than threefold from the mean (a range considered acceptable for most cell-based assays). 34,35 This performance was considered modest but acceptable.…”

Section: Resultsmentioning

confidence: 99%

High-Throughput Surface Liquid Absorption and Secretion Assays to Identify F508del CFTR Correctors Using Patient Primary Airway Epithelial Cultures

et al. 2019

View full text Add to dashboard Cite

High-throughput screening for drug discovery is increasingly utilizing cellular systems of high physiological relevance, such as patient primary cells and organoid cultures. We used 3D-cultured cystic fibrosis patient bronchial epithelial cells to screen for new small-molecule correctors of the disease-causing F508del mutation in CFTR. Impaired mucociliary clearance due to insufficient airway hydration is a hallmark of cystic fibrosis and we used a simple measure of surface liquid levels to quantify F508del CFTR correction in cultured bronchial epithelial cells. Two robust assay formats were configured and used to screen more than 100,000 compounds as mixtures or individual compounds in 96-well format. The corrector discovery success rate, as measured by the number of hits confirmed by an electrophysiology assay on patient primary bronchial epithelial cells, was superior to screens in cell lines expressing recombinant F508del CFTR. Several novel corrector scaffolds were discovered that when combined with the clinical corrector VX-809 delivered combination responses greater than double that of VX-809 alone. This work exemplifies the advantages of a disease-relevant readout and 3D-cultured patient primary cells for the discovery of new drug candidates.

show abstract

Section: Resultsmentioning

confidence: 99%

High-Throughput Surface Liquid Absorption and Secretion Assays to Identify F508del CFTR Correctors Using Patient Primary Airway Epithelial Cultures

et al. 2019

View full text Add to dashboard Cite

show abstract

“…It is not subject to copyright under 17 USC 2). Three critical assay design parameters, based on the NCATS Assay Guidance Manual, were selected for optimization: reaction time, substrate concentration, and enzyme concentration [15,16].…”

Section: Papain Cell-free Enzymatic Assaymentioning

confidence: 99%

Cross-platform Bayesian optimization system for autonomous biological assay development

Elder

Klumpp‐Thomas

Yasgar

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Current high-throughput screening assay optimization is often a manual and time-consuming process, even when utilizing design-of-experiment approaches. A cross-platform, Cloud-based Bayesian optimization-based algorithm was developed as part of the NCATS ASPIRE Initiative to accelerate preclinical drug discovery. A cell-free assay for papain enzymatic activity was used as proof-of-concept for biological assay development. Compared to a brute force approach that sequentially tested all 294 assay conditions to find the global optimum, the Bayesian optimization algorithm could find suitable conditions for optimal assay performance by testing only 21 assay conditions on average, with up to 20 conditions being tested simultaneously. The algorithm could achieve a seven-fold reduction in costs for lab supplies and high-throughput experimentation run-time, all while being controlled from a remote site through a secure connection. Based on this proof-of-concept, this technology is expected to be applied to more complex biological assays and automated chemistry reaction screening at NCATS, and should be transferable to other institutions.

show abstract

“…NCATS arms researchers with translational science information by making new methods, data, and information publicly available. For instance, the Assay Guidance Manual (AGM), as a procedure for data transparency and release in NCATS, resulted in the successful development of robust, early-stage drug discovery assays [ 62 ]. In addition, in the case of the availability of data, NCATS serves the pharmacological industry through PubChem [ 63 ] (small organic molecules and their activities against biological assays), the NCATS pharmaceutical collection [ 64 ] of active pharmaceutical ingredients and small molecules, and small molecule probes [ 65 ].…”

Section: Computational- and Wet Lab-based Assay Dbsmentioning

confidence: 99%

Applications of Genome-Wide Screening and Systems Biology Approaches in Drug Repositioning

Mohammadi

Benfeitas

Türkez

et al. 2020

Cancers

View full text Add to dashboard Cite

Modern drug discovery through de novo drug discovery entails high financial costs, low success rates, and lengthy trial periods. Drug repositioning presents a suitable approach for overcoming these issues by re-evaluating biological targets and modes of action of approved drugs. Coupling high-throughput technologies with genome-wide essentiality screens, network analysis, genome-scale metabolic modeling, and machine learning techniques enables the proposal of new drug–target signatures and uncovers unanticipated modes of action for available drugs. Here, we discuss the current issues associated with drug repositioning in light of curated high-throughput multi-omic databases, genome-wide screening technologies, and their application in systems biology/medicine approaches.

show abstract

Assay Guidance Manual: Quantitative Biology and Pharmacology in Preclinical Drug Discovery

Cited by 41 publications

References 12 publications

High-Throughput Surface Liquid Absorption and Secretion Assays to Identify F508del CFTR Correctors Using Patient Primary Airway Epithelial Cultures

High-Throughput Surface Liquid Absorption and Secretion Assays to Identify F508del CFTR Correctors Using Patient Primary Airway Epithelial Cultures

Cross-platform Bayesian optimization system for autonomous biological assay development

Applications of Genome-Wide Screening and Systems Biology Approaches in Drug Repositioning

Contact Info

Product

Resources

About