Preclinical Development of Geranylgeranyl Disphosphate Synthase Inhibitors as Ant

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DESCRIPTION (provided by applicant): The overall goal of the proposed studies is to establish the feasibility of moving our novel class of GGDPS specific inhibitors into clinical development for treatment of myeloma and metastatic disease of the bone. The specificity that a number of these novel non-nitrogen- containing bisphosphonates, most notably LWS-138, exhibit over the leading commercial alternatives makes them favorable candidates for further development aimed at clinical usage. Phase One of this project contains four specific aims designed to prove feasibility of this premise. These aims are formulated to allow a go/no-go decision on each of three potential lead compounds we have identified in our preliminary work. We plan to make enough of each member of our lead series for these studies (4-5 grams). We will concurrently carry out method development and validation for quantitative determination of each of these candidates in cell culture media, cell lysate, and mouse plasma. The primary feasibility studies will entail a combination of in vitro pharmacokinetic studies of metabolism, membrane permeability, and plasma protein binding; and in vivo efficacy studies in mouse xenograft breast and prostate cancer models. From these studies we will prioritize the compounds for further study in more elaborate models of metastatic bone disease as part of a Phase Two proposal. It was estimated that there would be approximately 500,000 new diagnoses of cancers of the breast, prostate or multiple myeloma in 2005, and that deaths from these cancers in that year would reach a total of 82,000. Nearly all of the patients who are somewhere between these two points in the disease progression will present with metastatic bone disease at some time. Metastatic disease confined to the skeleton is associated with a longer life expectancy than visceral metastasis but also with significant morbidity; therefore new therapies which could lessen the morbidity in this large group of patients would clearly benefit the public.