Bone-seeking proteasome inhibitors for myeloma

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DESCRIPTION (provided by applicant): Multiple myeloma (MM) is an incurable neoplasm characterized by devastating and progressive bone destruction. Standard chemotherapeutic agents have not been effective at significantly prolonging the survival of MM patients and these agents are typically associated with often severe, dose-limiting side effects. There is great need for methods to target the delivery of novel, effective cytotoxic agents specifically to bone, where myeloma cells reside. The long-term goal of this K01 proposal is to prepare Dr. Agyin, who has a strong synthetic chemistry background, to develop an independent career focused on the discovery of novel and innovative strategies aimed at selectively delivering therapeutic agents to the bone microenvironment for effective management of MM. In this proposal, the candidate outlines a plan to achieve this objective. Dr. Agyin will acquire skills in cancer and bone biology as they relate primarily to MM and develop a unique strategy to selectively deliver proteasome inhibitors (PS341 and MG262) to bone. Dr. Mundy, a world-renowned expert in myeloma and bone biology will serve as his mentor. Through this award, the candidate will design and synthesize novel PS341- and MG262-Bisphosphonate (PI-BP) conjugates and study their biological effects on MM both in vitro and in vivo. The candidate will also take didactic courses in biology, including Animal Models, Cancer Biology, Oncogenes and Tumor Suppressor Genes, and Molecular Oncology. Our hypothesis is that 1) the linking of bisphosphonates to proteasome inhibitors will target these hybrid compounds to myeloma cells in bone to achieve more effective local concentrations, and 2) that this will effectively kill tumor cells directly at the site of their growth, stimulate bone formation directly at the site of bone loss, and reduce side effects. The specific aims of the proposal are i) To design and synthesize novel PI-BP conjugates as a means of selective delivery of PS341 and MG262 to bone, ii) To synthesize C-14-and C-14/tritium-labeled PS341- and MG262-BP conjugates to study the bioavailability and homing capabilities of the conjugates in vivo, and iii) To study the proposed compounds in vitro and in vivo. The aims of this proposal will be addressed using multidisciplinary approaches including chemical synthesis and biological evaluation. These studies will serve to identify the most promising candidate prodrug to be subsequently tested in clinical trials as a novel treatment modality for MM.