Development of a high-throughput screen to detect the effects of both pre- and post-biotransformed compounds for enhanced content drug discovery workflows

Development of a high throughput screen to detect the effects of both preand postbiotransformed compounds for enhanced content drug discovery workflows Project Summary This Small Business Innovation Research Phase II project will build upon our successful Phase I demonstration that substrate free autobioluminescent signal generation can detect both the preand post biotransformed metabolic impacts of therapeutic compounds from a single plate based assayHerewe will leverage this technology to develop a panel of industry relevant autobioluminescent cell lines optimized for the detection of preand post biotransformed compound metabolic impacts and the identification of specific detoxification pathway activation using modern three dimensionalDmicrophysiological culture systemsThese products and their underlying technology will specifically address the National Institute of General Medical SciencesNIGMSrequest for novel in vivo and in vitro methods for predicting the safety and toxicities of pharmacologic agentsBy optimizing this technology to function within the industry preferredD microphysiological formatwe will address the critical need for new methods that can both identify compound toxicity and elucidate the mechanisms through which cells mitigate the compoundseffectsThe autonomous nature of this technology will increase toxicological data acquisition while preserving the critical advantage of presenting physiologicallyrelevant dataand reducing the cost of performance by eliminating substratesreducing complexitylimiting hands on operation timeobviating the need for sample destructionand reducing the potential for measurement errorThrough the validation of this technology at a scale relevant to tierdrug discovery screening and its comparative analysis against the existing gold standard ATP content assaythis revolutionary approach is poised to have a significant and immediate impact towards reducing the estimated $ B year in unnecessary expenditures made by pharmaceutical companies during their development of theof new compounds that fail at the Phase I clinical trial stage due to misidentification of toxicological effects during tierscreeningThis is possible becauseas demonstrated in our Phase I workthe use of our autobioluminescent technology overcomes the high economic and logistical costs of existingtraditionally bioluminescent cell s requisite chemical substrate additionwhich must co occur with each generation of signaland the intensive hands on time necessitated to scale cultures due to their requisite sample destruction concurrent with imagingSimilarlyour autobioluminescent technology also obviates the hurdles presented by fluorescent cell s susceptibility to autofluorescent signal inhibition and their tendency to remain active during downturns in cellular metabolism or even after cell deathThe technology and products developed in this effort will therefore be capable of significantly improving the throughput and effectiveness of microphysiological systems based tiercompound screening to improve the efficiency and economics of new compound developmentand ultimatelyconsumer safetyThis will allow them to thrive in a microphysiological system market that is predicted to maintain a compound annual growth rate ofto exceed $B globally by