Novel Inhibitors of PSMB and PSMB for the Treatment of Multiple Myeloma

Multiple myeloma is incurable hematologic malignancy with an expected median survival of years The proteasome inhibitors bortezomib carfilzomib and the recently approved ixazomib are a mainstay of current myeloma treatment Despite an initial response rate approaching to proteasome inhibitor containing combinations all patients relapse and eventually become resistant to any treatments We have discovered a distinct proteasome inhibitor LU which re sensitizes bortezomib and carfilzomib resistant cell lines and primary cells from myeloma patients to these FDA approved proteasome inhibitors and sensitizes myeloma to sub toxic doses of carfilzomib in mice The primary targets of all FDA approved inhibitors are the sites PSMB and PSMB of the proteasome The primary targets of LU are PSMB and PSMB i subunits Thus we hypothesize that PSMB and PSMB are novel targets in relapsed and refractory myeloma LU is protected by two patents which Dartmouth owns and agreed to license to InhiProt The specific aim of the phase I of the project is to improve potency and pharmacological properties of LU We will use standard medicinal chemistry approaches to achieve the milestone of developing a new highly specific compound which specifically inhibits PSMB and PSMB in bone marrow by andgt at mg kg and does not cross blood brain barrier In the phase II of the award we will conduct efficacy experiments in animal models of multiple myeloma and perform PK and ADMET studies We will test whether the lead synergizes with other anti myeloma agents We will solve structures of new inhibitor in complex with the proteasome and will use it to refine the lead In Americans were diagnosed with and will died from multiple myeloma MM an incurable cancer of bone marrow It is projected that by the number of new cases of MM in the U S will increase by ranking it third among cancers in the rate of growth of new cases Novel treatments for relapsed refractory myeloma are needed