Developing therapeutic inhibitors of CIB1 for breast cancer

DESCRIPTIONprovided by applicantBreast cancer is the most common malignancy in women living in the USwith more thannew cases diagnosed each yearand an estimatedwomen dying from the disease inGreater thanof these diagnoses are classified as triple negative breast cancerTNBCwhich is considered among the most aggressive breast cancer sub typeswith the worst prognosisTNBC is difficult to treat because pharmacologic approaches are limited to systemic chemotherapieswhich often fail due to high toxicity and drug resistanceThereforethe need for highly effective therapies against TNBC is acuteWe have identified a promising target for TNBCthe intracellular protein CIBwhich supports two of the most frequently activated oncogenic pathways in breast cancer PI K AKT and MEK ERKCIBdepletion simultaneously inhibits both pathwaysprofoundly killing human TNBC cells in culture and in vivoThusCIBdepletion dramatically shrinks tumors derived from a human TNBC cell line in a mouse xenograft modelThese results and the fact several CIBdepleted non transformed cell types and CIBknockout mice are relatively unaffected suggest that CIBis a safe targetTo advance CIBas an anticancer targetwe formed Reveris Therapeutics LLCIn collaboration with UNCandapos s Center for Integrative Chemical Biology and Drug Discovery directed by the PIDrStephen Fryewe identified via high throughput screeningmultiple diverse chemical series of small molecule CIBinhibitorsand are focusing on four hit compoundsInitial testing to date indicates that these compounds enter cellsbind CIBand or induce TNBC cell death with the expected properties and selectivityHere we propose firstto initiate hit to lead chemistry to optimize our current hitsWe will do this by establishing initia structure activity relationshipsSARfor each identified chemical seriesWe will then begin iterative optimization of their properties to arrive at a lead series with sufficient potency and selectivity for further pharmacologic target validationLeads will progress via advanced computer aided design and medicinal chemistrySecondwe will perform biologic and pharmacokinetic evaluationsCompounds will progress through in vitro assays to cellularADME and in vivo pharmacokinetic and efficacy assessments to support SAR and lead series selectionsWe expect that completion of these aims will lead to further pre clinical and eventually clinical studies of CIBtargeting in TNBC PUBLIC HEALTH RELEVANCEBreast cancerBCis the largest cause of cancer related deaths in women worldwideTriple negative breast cancerTNBCis an especially alarming form of breast cancer due to its resistance to hormone therapy and HERdirected agentsIn factno targeted therapy exists for TNBCThe intracellular proteinCIBappears to be an outstanding potential therapeutic target for several types of breast and other cancersincluding TNBCBecause of the pressing need in TNBCReveris Therapeutics and its academic collaborators seek to accelerate hit to lead optimization of small molecule inhibitors of CIBfor preclinical testing in this disease