Development of Notch Pathway Specific Inhibitors as Targeted Therapeutics for Cancer

ABSTRACT The incidence of esophageal adenocarcinomaEAChas increased more thanfold in the United States over the pastyearsUnfortunatelythe prognosis for EAC patients is poor with an overallyear survival rate ofDue to the lack of effective screening optionsEAC patients are often diagnosed late with advanced diseasewhere theyear survival rate is onlyCurrent standard of care treatmentsconsisting of neoadjuvant chemotherapy followed by surgical resection are ineffective in the majority of casesThereforea substantial unmet medical need exists to identify and successfully drug not only the drivers of EAC but also the signaling pathways that underlie resistance to chemotherapyHereinwe present a clear role for Notch signaling in EAC as critical for the maintenance of the neoplastic phenotype conferring resistance to neoadjuvant chemotherapy by driving a cancer stem cell phenotypeThe Notch pathway is considered to be a highly attractive and sought after target with no specific pathway inhibitorsNotch signaling involves a series of proteolytic cleavage events that releases the Notch intracellular domainNICDfrom the cell surfaceNICD is critical for the formation of an active Notch ternary complexNTCThe NTC is composed of NICDCSLand MastermindMAMLwithout all of these components together the NTC is unable to activate transcriptionHereinwe present our novel approach to identify a drug binding pocket in the NTC and then develop a class of small molecule inhibitors that prevent active NTC formation with the aim of complementing and or replacing existing EAC therapiesWe have discovered a novel class of Notch inhibitors and that specifically bind to a pocket in the CSL NICD interface and prevents binding of MAML and thereby inhibiting Notch signalingWe also present our validation of the mechanism of action and in vivo efficacy of early lead compoundsWe also outline the significant progress made in lead optimization that identified analogs with improved potencyandgtfoldand in the identification of new scaffolds via molecular modeling scaffold hoppingIn this Phase I SBIR applicationwe propose to evaluate the in vivo efficacy and therapeutic window for the new analogsCompletion of these studies will yield a preclinical candidate for IND enabling studiesStemSynergy TherapeuticsIncSSTIis a biopharmaceutical company whose focus is on the discoverydevelopmentand commercialization of drugs targeting WNTHedgehog and Notch signaling pathwayspathways critical to stem cell and cancer stem cellsThe Notch inhibitors identified in this proposaland analogsrepresent new chemical entities and a patent application has been filedSSTI has an exclusive license to develop this compound series and the expertise and the opportunity to bring to market a first generation Notch inhibitor that would capture a significant share of the global market for cancer drugsnot just to treat EACbut also for other Notch driven cancers NARRATIVE The number of patients with esophageal adenocarcinomaEAChas tripled over the pastyearsIn the majority of patientsEAC tumors do not respond well to chemotherapy and therefore have a poor prognosis for survivalNotch signaling represents a critical mechanism of resistance to chemotherapy and this application describes the preclinical development of a novel class of Notch inhibitors toward clinical trials