Improving the Distribution of Geranylgeranyl Diphosphate synthase inhibitors.

描述(申请人提供)：这些研究的目标是开发一种基于抑制香叶基二磷酸合成酶(GGDPS)的激素难治性前列腺癌的治疗方法。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，在体外显示出对GGDPS的高度有效和特异的抑制作用。这些化合物不包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看到了我们目前系列的先导化合物TTI-138的一些有趣的体内抗肿瘤活性，而在所研究的剂量下基本上没有显示出毒性的迹象。这与目前使用的双膦酸唑来膦(Zometa，Novartis)等药物形成鲜明对比，后者仅在临床无法达到的浓度下，在骨骼以外的部位显示出抗前列腺癌移植瘤的活性。虽然TTI-138确实显示了一些效果，但在体外模型中，我们也看到这种药物对破骨细胞性骨重新吸收的实质性抑制。我们认为，结合体外和体内试验进行进一步的结构活性研究将有助于开发具有更理想特性的制剂，包括在原发肿瘤模型中具有较低的骨亲和力和较高的活性。在这里，我们建议进行第一阶段研究，以证明这种方法在前列腺癌治疗中的可行性。这些可行性研究将包括一项大型计算机模拟研究，该研究设计了酶活性部位内的抑制剂。然后，我们将进行模型所示化合物的合成，并在一组扩大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作用。我们将同时在两种骨亲和力模型中测试它们。这些生物筛选将被用来为进一步改进设计的化合物提供信息。如果我们能找到具有低骨靶向性的高度特异的抑制剂，我们将把已确定的化合物转移到第二阶段研究，包括小鼠前列腺癌异种移植模型、药效学/药代动力学分析、体内骨亲和力模型和初步毒理学。考虑到大量前列腺癌患者，我们认为具有低毒和良好副作用的化合物可以在这种疾病的治疗中找到重要的利基。这些研究将是倡导针对GGDPS的非骨相关癌症适应症的治疗设计的第一个例子。公共卫生相关性：相关性据估计，2008年将有大约186,000例新诊断的前列腺癌病例，该年死于该疾病的总人数将接近29,000例。尽管有早期疾病的治疗选择，但许多患者最终将进展为一种高度转移性的雄激素非依赖性前列腺癌，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往往对标准治疗方案产生抗药性。在这项提案中，我们主张通过抑制一种未被开发的生物过程来开发药物，这一过程已知对前列腺癌的进展很重要。HRPC的新疗法可能会对这一患者群体产生重大影响

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