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

Project Summary Abstract Multiple Myeloma MM is the second most common form of blood cancer and remains an incurable and deadly disease Proteasome inhibitor PI therapy is a cornerstone in the treatment of MM but resistance to this class of agent is an emerging challenge in the clinic New therapeutic approaches that specifically target resistance are needed to maximize responses and ultimately produce cures We have identified a hit stage drug compound E that selectively kills MM cells over normal cells restores the activity of PIs in resistant MM cells and cures more that of mice with MM without any signs of toxicity We have designed new derivatives of E that have optimized pharmaceutical properties The specific goals of the proposed project are to conclusively demonstrate increased metabolic stability and anti MM activity of optimized E derivatives and to show superior in vivo activity of optimized derivatives using a mouse model of MM Compounds will be tested as single agents and in combination with FDA approved PIs These study aims are based on strong preliminary medicinal chemistry work that identified structure activity relationships SAR of compound E This information has enabled the strategic design of the derivatives that we will test in the proposed study The proposed experiments capitalize on industry standard assay systems for measuring pharmacological properties of new drugs in vitro including metabolic stability in blood plasma and liver microsomes and assays directly measuring drug metabolism by the catechol O methyltransferase COMT enzyme In vitro assays for measuring anti MM activity and predicting toxicity include the use of panels of genetically diverse PI sensitive and resistant MM cells and a variety of normal blood and fibroblast cell types For evaluating the performance of novel derivatives in vivo we will use an established model of experimentally induced MM that accurately recapitulates the human MM pathology in NOD SCID IL Rgammanull NSG mice Through the use of these tools and predictions based on a breadth of preliminary data it is our expectation that this work will deliver a promising new compound for the treatment of refractory MM Narrative Relevance Proteasome inhibitors are cornerstone therapies in the treatment of Multiple Myeloma MM However resistance limits their effectiveness and MM remains incurable today Our project will develop 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