Alpha to the omega: modifications of 1,4-triazole bisphosphonates as potential therapeutics for multiple myeloma

Multiple myeloma is a bone marrow cancer and is responsible for the death of approximately 12,000 people yearly in the United States. Multiple myeloma is the second most common blood cancer and is characterized by the over-production and secretion of monoclonal antibodies. This can cause patients to have immune dysfunction, bone destruction, and ultimately kidney failure. Currently, multiple myeloma is not considered curable. One ideal treatment for this disease would be to target the Rab proteins, which play a role in trafficking of monoclonal proteins. This might be done by targeting the geranylgeranylation of Rab proteins by diminishing the synthesis of the IBP substrate geranylgeranyl diphosphate (GGPP) via inhibition of the enzyme geranylgeranyl diphosphate synthase (GGDPS). Our research team has developed one class of GGDPS inhibitors, known as isoprenoid triazole bisphosphonates, and found them to be potent and selective towards GGPDS inhibition in the nM concentration range. A series of modifications at different locations of the bisphosphonates has been achieved, and the new compounds have both higher potency towards GGDPS inhibition. Compounds modified at the ω position lacked biological activity but were able to alter in vivo biodistribution through linkage to a drug delivery agent. A series of modifications at the α position was accomplished, and these compounds were demonstrated to have an impact on GGPDS. These findings encourage future efforts to improve cellular entry of these bisphosphonates and to enhance potency by incorporating these modifications into other isoprenoid triazole bisphosphonate structures.