Geranylgeranyl diphosphate synthase inhibitor therapy for multiple myeloma

项目摘要 多发性骨髓瘤(MM)是一种无法治愈的骨髓(BM)癌症，其特征是产生 单克隆蛋白(MP)。耐药性和非靶向效应的发展限制了目前的疗效 可用代理。因此，迫切需要新的治疗策略，包括药物输送策略。 需要的。我们重点研究了通过抑制MP在MM细胞中的转运来靶向MP的新策略。 香叶基香叶二磷酸合成酶(GGDPS)。GGDPS抑制剂(GGSI)干扰RAB 香叶基香叶化，导致细胞内MP积聚，内质网应激，诱导所有三个臂 未折叠的蛋白反应通路最终导致多发性骨髓瘤细胞死亡。我们的GGSI开发工作已经完成 重点研究了异戊二烯类三唑双膦酸盐和我们的结构-功能研究确定了 类异戊二烯链长和立体化学影响抑制剂的效力以及体内的生物分布。 我们的主要GGSI的临床前研究显示了关键的类药物特性，包括代谢 稳定性，延长的血浆半衰期，全身分布，蛋白质香叶素的体内干扰和 小鼠多发性骨髓瘤异种移植模型的抗肿瘤效果。剂量发现和毒理学研究显示肝脏 毒性为剂量限制，对血液、肾脏、心脏或神经功能无影响。我们的预赛 研究表明，改变透明质酸(HA)聚合物的相对分子质量可以限制肝脏摄取 并增强骨髓的摄取，使MM细胞容易摄取HA。因此，我们假设治疗方法 通过将我们的GGSI连接到HA聚合物，可以优化GGSI的潜力，从而增强GGSI的交付 GGSI对骨髓和最小化肝脏摄取和我们的初步研究支持这一假说。对这件事 最终，我们将合成基于我们的先导化合物的新型GGSI，但要么在α- 允许与HA偶联或通过磷酸盐前药形式连接到HA的位置(目标1)我们将执行 详细的结构研究，包括结合抑制剂的蛋白质结晶学研究，以澄清 这些GGSI与靶酶(Aim 1)相互作用的机制将有助于设计 未来几代GGSI。我们将确定药代动力学/药效学概况和 新型可连接GGSI和相应的HA聚合物结合物的生物分布模式(目标2)。我们 将研究调节GGSI肝脏摄取和毒性的机制。铅GGSI-HA的疗效观察 结合物将在建立髓外和髓外疾病模型的异种移植研究中进行评估 参与(目标3)。评价GGSI治疗与临床应用结合的体内外研究 将执行反MM代理。虽然我们目前的重点是开发治疗多发性骨髓瘤的GGSI疗法， 这些研究具有额外的意义，因为这种药物结合到HA的新方法将改变 生物分布可应用于治疗MM的其他临床相关药物的输送。

Project Summary Multiple myeloma (MM) is an incurable bone marrow (BM) cancer characterized by the production of monoclonal protein (MP). Development of drug resistance and off-target effects limits the efficacy of currently available agents. Therefore, novel therapeutic strategies, including drug delivery strategies, are urgently needed. We have focused on the novel strategy of targeting the trafficking of MP in MM cells by inhibiting the enzyme geranylgeranyl diphosphate synthase (GGDPS). GGDPS inhibitors (GGSIs) disrupt Rab geranylgeranylation, which results in intracellular MP accumulation, ER stress, induction of all three arms of the unfolded protein response pathway and ultimately MM cell death. Our GGSI development efforts have focused on isoprenoid triazole bisphosphonates and our structure-function studies have determined that isoprenoid chain length and stereochemistry impact inhibitor potency as well as in vivo biodistribution. Preclinical studies with our lead GGSIs have demonstrated key drug-like properties, including metabolic stability, prolonged plasma half-life, systemic distribution, in vivo disruption of protein geranylgeranylation and anti-tumor efficacy in a mouse MM xenograft model. Dose-finding and toxicology studies revealed hepatic toxicity as dose-limiting with no effects on hematologic, renal, cardiac or neurologic function. Our preliminary studies revealed that altering the molecular weight of a hyaluronic acid (HA) polymer can limit hepatic uptake and enhance BM uptake and that MM cells readily take up HA. We therefore hypothesize that the therapeutic potential of GGSIs can be optimized via linkage of our GGSIs to HA polymers, thus enhancing delivery of GGSI to the BM and minimizing hepatic uptake and our preliminary studies support this hypothesis. To this end, we will synthesize novel GGSIs that are are based upon our lead compound but either modified at the α- position to allow conjugation to HA or linked to HA through phosphonate prodrug forms (Aim 1) We will perform detailed structural studies, including protein crystallography studies with bound inhibitors, to clarify the mechanisms by which these GGSIs interact with the target enzyme (Aim 1) which will aid in the design of future generations of GGSIs. We will determine the pharmacokinetic/pharmacodynamic profiles and biodistribution patterns of the novel linkable GGSIs and the corresponding HA polymer conjugates (Aim 2). We will investigate the mechanisms regulating GGSI hepatic uptake and toxicity. The efficacy of the lead GGSI-HA conjugates will be assessed in xenograft studies which model extramedullary and medullary disease involvement (Aim 3). In vitro and in vivo studies evaluating the combination of GGSI therapy with clinically used anti-MM agents will be performed. While our current focus is to develop GGSI therapy for treatment of MM, these studies have added significance because this novel approach of drug conjugation to HA to alter biodistribution could be applied to the delivery of other clinically relevant agents for treatment of MM.