Improving the Distribution of Geranylgeranyl Diphosphate synthase inhibitors.
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AbstractDESCRIPTION (provided by applicant): The goal of these studies is the development of a treatment for hormone refractory prostate cancer based on the inhibition of an enzyme geranygeranyl disphosphate synthase (GGDPS). We have developed a group of proprieta ry bisphosphonates containing isoprene substructures that demonstrate highly potent and specific inhibition of GGDPS in vitro. These compounds do not contain the hydroxyl group or the nitrogen substructure of the current clinical agents. We have recently s een some interesting in vivo antitumor activity for our current lead compound of the series, TTI-138 in a xenograft model of prostate cancer while showing essentially no signs of toxicity at the doses studied. This is in contrast to the currently used bisp hosphonates such as zoledronate (Zometa, Novartis) which demonstrate activity against prostate cancer xenografts, at sites other than bone, only at clinically unachievable concentrations. While TTI-138 does show some efficacy we also see substantial inhibi tion of osteoclastic bone reasorption with this agent in an ex vivo model. We feel that further structure activity studies using a combination of in vitro and in vivo assays would allow development of an agent with more desirable characteristics including lower bone affinity and higher activity in primary tumor models. Here we propose Phase I studies to prove the feasibility of this approach in prostate cancer treatment. These feasibility studies will be comprised of a large computer modeling study designed inhibitors within the active site of the enzyme. We will then carry out the synthesis of the compounds indicated by the modeling and test them in an expanded set of three prostate cancer cell lines for inhibition of GGDPS, migration and cell growth. We wi ll concurrently test them in two models of bone affinity. These biological screens will be used to inform further refinement of the designed compounds. If we can identify highly specific inhibitors with low bone targeting we would move the compounds identi fied into Phase II studies entailing mouse xenograft models of prostate cancer, pharmacodynamic/pharmacokinetic analysis, in vivo models of bone affinity, and preliminary toxicology. Given the large number of patients who present with prostate cancer we fe el compounds with low toxicity and favorable side-effects profiles can find a significant niche in the treatment of this disease. These studies would be the first examples advocating design of treatments targeting GGDPS for a non-bone related cancer indica tion. PUBLIC HEALTH RELEVANCE: Relevance It was estimated that there would be approximately 186,000 new diagnoses of prostate cancer in 2008, and that deaths from this disease in that year will total almost 29,000. Despite treatment options for early disea se stages many patients will eventually progress to a highly metastatic androgen independent form of this disease termed Hormone Refractory Prostate Cancer (HRPC). Despite some recent advances in treatment HRPC's often become resistant to standard treatmen t regimens. In this proposal we advocate developing drugs based on inhibiting an un exploited biological process that is known to be important to prostate cancer progression. New therapies for HRPC could have large impacts on this patient population
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