Project Grant R44GM154583

EMOA: A MULTI-OMIC SERVICE FOR MECHANISM OF ACTION DETERMINATION IN DRUG SCREENING - SUMMARY THE PATHWAY TO A SUCCESSFUL DRUG DEVELOPMENT PROGRAM IS GETTING MORE CHALLENGING AND EXPENSIVE EVERY YEAR. CURRENTLY, BRINGING A SINGLE THERAPEUTIC COMPOUND TO MARKET STARTS IN EARLY DISCOVERY BY THE BROAD SCREENING OF TENS OF THOUSANDS OF MOLECULES AND IS USUALLY FOLLOWED BY A SERIES OF PRECISE ASSAYS TO REDUCE THE NUMBER OF COMPOUNDS TO A HANDFUL OF CANDIDATES. FOR THESE CANDIDATES TO ENTER CLINICAL TRIALS, REGULATORY AGENCIES ARE NOW DEMANDING THAT THE MOLECULAR MECHANISM OF ACTION IS WELL UNDERSTOOD. TRADITIONALLY, THAT MEANT YEARS OF BASIC RESEARCH USING LOW THROUGHPUT AND COMPLICATED ASSAYS WITHIN A RESEARCH PROGRAM. THE COMBINATION OF THE SECONDARY SCREENING ASSAYS TOGETHER WITH THE BASIC RESEARCH NEEDED TO UNDERSTAND THE MECHANISM OF ACTION CAN NOT ONLY BE VERY COSTLY, BUT ALSO CREATE DELAYS FOR THESE NEW THERAPEUTIC AGENTS TO REACH PATIENTS. CURRENTLY, SOME OF THE SECONDARY SCREENS MEASURE GENE EXPRESSION LEVELS USING TRANSCRIPTOMICS, SHOTGUN PROTEOMICS AS WELL AS A COMBINATION OF OTHER OMICS APPROACHES. RECENTLY, REGULATION OF TRANSLATION HAS EMERGED AS A NEW MECHANISM BY WHICH DRUGS CAN ACT ON CELLULAR FUNCTIONS. FOR EXAMPLE, THE MTOR PATHWAY THAT REGULATES CELL PROLIFERATION, APOPTOSIS, AUTOPHAGY, AND OTHER CELLULAR PROCESSES, PARTICIPATES IN MULTIPLE CELL-SIGNALING PATHWAYS DIRECTLY INFLUENCING TRANSLATION OF SPECIFIC MRNAS. SEVERAL COMPOUNDS INHIBITING THE MTOR PATHWAY HAVE BEEN IDENTIFIED, INCLUDING TORIN 1 AND SAPANISERTIB, AND THEIR MECHANISM OF ACTION HAVE BEEN SHOWN TO BE THROUGH DIRECT INHIBITION OF TRANSLATION. ECLIPSEBIO'S ERIBO COUNT WILL BE MODIFIED FOR HIGHER THROUGHPUT SCREENING OF SMALL MOLECULES AND USED TO COMMERCIALLY DEPLOY A SECONDARY DRUG SCREEN PLATFORM, CALLED EMOA, THAT WILL USE BOTH TRANSCRIPTOMICS AND TRANSLATOMICS TO RAPIDLY NARROW DOWN THE NUMBER OF CANDIDATE MOLECULES OF INTEREST. PHASE I WILL FOCUS ON SCREENING FOR A MONOCLONAL ANTIBODY THAT WILL REDUCE SIGNAL TO NOISE AS WELL AS IDENTIFY BASIC PARAMETERS, SUCH AS SEQUENCING DEPTH AND LIBRARY COMPLEXITY, THAT WILL ALLOW FOR SUCCESSFUL IDENTIFICATION OF CANDIDATE COMPOUNDS WITH PRECISE MECHANISM OF ACTION INFORMATION. PHASE II WILL INCORPORATE THE PHASE I DEVELOPMENT AND FINDINGS TO ALLOW DRUG SCREENING VIA THE EMOA PLATFORM TO BE PERFORMED IN A 96-WELL PLATE, ALLOWING FOR MID THROUGHPUT SCREENING. IN ADDITION, EMOA WILL BE USED TO SCREEN A LIBRARY OF ~1,500 DISTINCT, CLINICALLY RELEVANT COMPOUNDS WITH DETAILED MECHANISM OF ACTION. THIS WILL BE USED TO TRAIN A MACHINE LEARNING MODEL THAT WILL ENABLE CLASSIFICATION OF UNKNOWN COMPOUNDS FOR RAPID IDENTIFICATION OF THEIR MECHANISM OF ACTION. THIS DRUG SCREENING PLATFORM WILL BE FURTHER DEVELOPED TO INCLUDE A RICH USER INTERFACE ENABLING CUSTOMERS TO BETTER UNDERSTAND THEIR NEW THERAPEUTICS. ECLIPSEBIO WILL PROVIDE THE EMOA PLATFORM AS A WHITE-GLOVE SERVICE FOR BIOTECH AND PHARMA TO SHORTEN THEIR RESEARCH CYCLE, PROVIDING BETTER COMPOUNDS TO PATIENTS IN CLINICAL TRIALS.