
Development of a High-Throughput Screen to Detect the Effects of Both Pre- and Post-Biotransformed Compounds for Enhanced Content Drug Discovery WorkflowsAward last edited on: 12/21/2017
Sponsored Program
SBIRAwarding Agency
NIH : NIGMSTotal Award Amount
$1,145,563Award Phase
2Solicitation Topic Code
-----Principal Investigator
Gary S SaylerCompany Information
Phase I
Contract Number: 1R43GM112241-01A1Start Date: 7/1/2015 Completed: 12/31/2015
Phase I year
2015Phase I Amount
$149,051Public Health Relevance Statement:
Public Health Relevance:
The drug discovery process requires that upwards of 10,000 molecules be screened for each new lead compound developed and relies upon an expensive and time consuming combination of in vitro cell culture-based and in vivo whole animal-based models to identify, validate, and ensure the safety of any resulting potential therapeutic agents. This process is frustratingly exacerbated by an unfortunate dichotomy whereby the inexpensive in vitro cell culture systems used for tier 1 screening contribute to failures due to their inabiliy to model the complexity and parallel systems interaction inherent in whole animal models (which are responsible for up to 92% of new compound failures at the clinical level) and because they are not capable of demonstrating species-specific effects. To overcome these detractions and develop an improved tier 1 screening system that reduces the cost and time required for new compound evaluation, 490 BioTech proposes to develop a panel of multiple continuously bioluminescent human cell lines that will permit the simultaneous monitoring of each line to ascertain both the individual effects of compound treatment as well as the downstream effects of a compound's biotransformed metabolic breakdown products in real-time.
Project Terms:
Address; Animal Model; Animal Testing; Animals; Bacterial Luciferases; base; Biological Assay; Biological Availability; Biological Markers; Bioluminescence; Brain Stem; Cell Culture System; Cell Culture Techniques; Cell Line; cell type; Cells; Chemicals; Clinical; Complex; cost; cytotoxic; cytotoxicity; Data; design; Detection; Development; diacetyldichlorofluorescein; drug discovery; Drug Metabolic Detoxication; Economics; Eligibility Determination; Employment; Engineering; Ensure; Enzymes; Equipment; Evaluation; Failure (biologic function); Firefly Luciferases; Glutathione; Growth; Health; Heart; high throughput screening; Histocompatibility Testing; Human; Human Cell Line; human tissue; improved; In Vitro; in vivo; Individual; Lead; Light; light emission; Luc Gene; luciferin; Lung; Mandatory Testing; Marketing; Metabolic; Metabolic Biotransformation; Methods; Modeling; Monitor; National Institute of General Medical Sciences; novel; Organism; Output; Pancreas; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Positioning Attribute; Preclinical Drug Evaluation; Process; programs; public health medicine (field); public health relevance; Reaction; Reactive Oxygen Species; Regimen; Reporter; research and development; research clinical testing; response; Reverse Transcription; Safety; screening; Screening procedure; Series; Signal Transduction; Small Business Innovation Research Grant; Staging; Stem cells; Stream; System; T47D; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Toxicology; Transcript; transcriptomics; Variant; Visual
Phase II
Contract Number: 2R44GM112241-02Start Date: 00/00/00 Completed: 00/00/00
Phase II year
2017(last award dollars: 2018)
Phase II Amount
$996,512Public Health Relevance Statement:
Project Narrative Failure to identify the toxicity of pharmaceutical compounds such as Mercks Vioxx, Bayers Baycol, and Wyeths FenPhen have caused consumers to be injured or killed by the drugs that were supposed to help them, and resulted in negative publicity and legal fees costing billions of dollars for the companies that produced them. While pharmaceutical companies have significantly enhanced their early stage toxicity screening regimens by transitioning to complex cell culture systems that can better identify new compounds toxicological effects on the human body to avoid repeating these mistakes, the use of these systems has increased the cost of new drug development to a level that is unsustainable for both consumers and the companies themselves due to a lack of technologies capable of economically identifying toxicity in these modern systems. In this Phase II R&D effort, 490 BioTech proposes to implement a novel toxicological screening technology based upon a synthetic luciferase genetic construct that links cellular health to the autonomous production of light in the visible spectrum to improve toxicity data acquisition by increasing the throughput and reducing the cost of modern pharmacological development assays while preserving their increased level of safety.
Project Terms:
Address; Affect; assay development; base; Biological Assay; Biotechnology; Cardiac; Cell Culture System; Cell Culture Techniques; Cell Death; Cell Line; Cell model; cell type; Cells; cerivastatin; Chemicals; Coculture Techniques; comparative; Complex; cost; CYP1A2 gene; CYP2B6 gene; CYP3A4 gene; cytotoxic; Data; data acquisition; Detection; Development; Dimensions; drug development; drug discovery; Drug Industry; Drug Metabolic Detoxication; drug metabolism; Early Diagnosis; Economics; Effectiveness; EPHX1 gene; Epithelial; established cell line; Evaluation; Expenditure; Failure; Fees; Generations; Genetic; Gold; Growth; Health; high throughput screening; Human; Human Biology; Human body; Image; improved; In Vitro; in vivo; Industrialization; Industry; injured; Kidney; Killings; Legal; Libraries; Light; Link; Liver; Logistics; Luciferases; Measurement; Metabolic; Metabolism; Methods; Modernization; NAT1 gene; National Institute of General Medical Sciences; Nature; novel; novel therapeutics; operation; Organ; Output; pancreatic cell line; Pathway interactions; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Physiological; Physiology; Predisposition; Prodrugs; Production; Regimen; Reporter; research and development; Research Personnel; Rofecoxib; Safety; Sampling; scaffold; screening; Signal Transduction; Small Business Innovation Research Grant; System; Technology; technology validation; Therapeutic; three dimensional cell culture; Time; Tissues; Toxic effect; Toxicity Tests; Toxicology; Vascular Endothelium; Work