Improving the Distribution of Geranylgeranyl Diphosphate synthase inhibitors.

描述（由申请方提供）：这些研究的目的是开发一种基于抑制酶香叶基香叶基二磷酸合酶（GGDPS）的激素难治性前列腺癌治疗方法。我们已经开发了一组专有的含有异戊二烯亚结构的双膦酸盐，其在体外表现出对GGDPS的高效和特异性抑制。这些化合物不含当前临床药物的羟基或氮亚结构。我们最近在前列腺癌的异种移植模型中观察到我们目前的系列先导化合物TTI-138的一些有趣的体内抗肿瘤活性，同时在所研究的剂量下基本上没有显示出毒性迹象。这与目前使用的双膦酸盐如唑来膦酸盐（Zometa，Novartis）形成对比，唑来膦酸盐仅在临床上无法达到的浓度下在骨以外的部位显示出对前列腺癌异种移植物的活性。虽然TTI-138确实显示出一些功效，但我们也在离体模型中观察到该药剂对骨细胞骨再吸收的实质性抑制。我们认为，使用体外和体内测定的组合的进一步结构活性研究将允许开发具有更期望的特征的药剂，包括在原发性肿瘤模型中较低的骨亲和力和较高的活性。在这里，我们提出了I期研究，以证明这种方法在前列腺癌治疗的可行性。这些可行性研究将包括在酶的活性位点内设计抑制剂的大型计算机建模研究。然后，我们将进行由建模指示的化合物的合成，并在扩展的三种前列腺癌细胞系中测试它们对GGDPS、迁移和细胞生长的抑制。我们将同时在两种骨亲和力模型中测试它们。这些生物筛选将用于进一步改进设计的化合物。如果我们能够鉴定出具有低骨靶向的高度特异性抑制剂，我们将把鉴定出的化合物转移到II期研究中，该研究需要前列腺癌的小鼠异种移植模型、药效学/药代动力学分析、骨亲和力的体内模型和初步毒理学。考虑到大量的前列腺癌患者，我们认为具有低毒性和良好副作用的化合物可以在这种疾病的治疗中找到一个重要的利基。这些研究将是倡导设计靶向GGDPS治疗非骨相关癌症适应症的第一个例子。公共卫生相关性：据估计，2008年将有大约186，000例新的前列腺癌诊断，该年死于该疾病的人数将达到近29，000人。尽管有早期疾病阶段的治疗选择，但许多患者最终将进展为这种疾病的高转移性雄激素非依赖性形式，称为激素难治性前列腺癌（HRPC）。尽管最近在治疗方面取得了一些进展，但HRPC通常对标准治疗方案产生耐药性。在这个提案中，我们提倡开发基于抑制已知对前列腺癌进展重要的未开发生物过程的药物。HRPC的新疗法可能对该患者人群产生重大影响

DESCRIPTION (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 proprietary 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 seen 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 bisphosphonates 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 inhibition 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 will 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 identified 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 feel 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 indication. 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 disease 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 treatment 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