Proteasome inhibitor re-sensitizing molecules for treatment of refractory multiple myeloma

Project Summary Abstract Multiple MyelomaMMis the second most common form of blood cancer and remains an incurable and deadly diseaseProteasome inhibitorPItherapy is a cornerstone in the treatment of MMbut resistance to this class of agent is an emerging challenge in the clinicNew therapeutic approaches that specifically target resistance are needed to maximize responses and ultimately produce curesWe originally identified hit stage compoundEthat selectively killed MM cells over normal cellsrestored the activity of PIs in resistant MM cellsand showed early signs of anti MM activity in a mouse model without any signs of toxicityIn the Phasecomponent of the project we engaged in a medicinal chemistry program that delivered a significantly more potent lead moleculeEFCwith improved drug like propertiesrobust in vivo efficacyand a strong patent positionFurthermorePhaseidentified protein disulfide isomerasePDIas the molecular target of this new class of small moleculePDI regulates protein folding and is therefore a rational drug target for MMwhich is a cancer that produce mass amounts of protein and is highly sensitive to disruption in protein homeostasisDespite this rationaleno PDI inhibitors have advanced to clinical trials in humansprimarily due to limitations in the in vitro PDI assays that are used in drug discoveryThe specific goals of the Phaseproject areto complete the chemical optimization of EFCto further improve its pharmaceutical properties and enhance oral bioavailabilityto demonstrate the anti MM efficacy of optimized EFCin multiple mouse models of MMandto conduct dose range finding maximum tolerated dose determining studies along with toxicokinetics in ratsThese study aims are based on strong preliminary data and a large scale medicinal chemistry program that identified key structure activity relationshipsSARand a potent PDI inhibitorThis information has enabled the strategic design of a short list of derivatives that we will test in the proposed studyIndustry standard ADME assays and pharmacokinetics will be used to evaluate new EFCderivativeand established mouse models of MM that recapitulate the human pathology and predict clinical efficacy will be usedIndustry standard dose range finding studies will facilitate formal GLP compliant toxicology that will enable an IND application to the FDAThrough the use of these toolsand predictions based on a breadth of preliminary datait is our expectation that this work will deliver a promising new drug candidate for the treatment of refractory MM NarrativeRelevanceProteasome inhibitors are cornerstone therapies in the treatment of Multiple MyelomaMMHoweverresistance limits their effectiveness and MM remains incurable todayWe have discovered a new class of drug that targets resistant MM and enhances the activity of proteasome inhibitors to improve the duration and quality of life for MM patients