SQSTM p targeted Small Molecules for Multiple Myeloma Disease

Despite the introduction of new anti multiple myeloma MM treatment regimens such as Bortezomib a top best selling cancer drug high MM relapse rates and drug resistance as well as problematic neuropathy and thrombocytopenia side effects continue to plague the current therapies Furthermore MM patients never respond to Bortezomib treatment Particularly osteolytic bone diseases and renal failure resulting from hyperparaproteinemia and hypercalcemia have been the major serious sequelae that are inextricably linked with MM tumor progression So far MM disease remains the second most common hematological malignancy in the U S and incurable with a median survival of to years Thus novel MM drug targets and new small molecule probes are in critical need both to understand the disease associated pathways and to facilitate anti MM drug discovery This Fast Track proposal seeks support for acceleration of FDA IND enabling preclinical evaluations of the developed high efficacy low toxicity small molecules targeting the protein p sequestosome SQSTM so called p ZZ inhibitors The scientific basis for p ZZ inhibitors as a novel anti MM pharmacotherapy includes i the innovative discovery of first p ZZ antagonist small molecules exhibiting significant inhibition of human MM cell growth as reported in our recent publications and patents ii the solid experimental confirmation of p target specificity revealing that down regulation or deletion of p in marrow stromal cells significantly decreased expression levels of PKC VCAM TNF and IL and also decreased the stromal cell support of MM cell growth iii the strong experimental verification showing that ZZ domain of p is specifically required for stromal cell support of MM cell growth and osteoclast activation through atypical PKC NF B MAPK and IL production iv the discovered p ZZ small molecule inhibitors demonstrated promising drug PK PD bioavailability and low toxicity profiles and can significantly inhibit MM tumor growth andgt compared with the control group in in vivo human MM xenograft murine model and v p ZZ small molecules induce dramatic new bone formation selectively in MM containing bones in an immunocompetent mouse model Thus the goal of the NIH Fast Track is to carry out IND enabling preclinical research and development work to advance the discovered reported small molecule drug candidates to the next stage for undertaking scale up chemistry synthesis and IND enabling toxicology and efficacy investigations Bringing drug candidates to the defined milestones will fast track commercialization opportunities via co development partnerships with major pharma biotech companies and also significantly enhance the chances of attracting additional private financial investments leading ultimately to multiple myeloma disease drug clinical trials ID Pharma LLC seeks Fast Track funding support to accelerate FDA IND enabling in vivo multiple myeloma MM efficacy and toxicity pharmacokinetics pharmacodynamics PK PD pre clinical investigations of the discovered p ZZ small molecules inhibitors for anti MM drug Randamp D The long term goal is to develop viable small molecule medications for rapid entrance into MM disease clinical trials