Geranylgeranyl diphosphate synthase inhibitor therapy for multiple myeloma

香叶基香叶基二磷酸合酶抑制剂治疗多发性骨髓瘤

• 批准号: 10180333
• 负责人: Sarah A Holstein
• 金额: $ 51.52万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10180333
• 关键词: AGFG1 gene; Abbreviations; Antibodies; Apoptosis; Biodistribution; Bone Marrow; Cell Death; Cell membrane; Cells; Clinic; Clinical; Crystallography; Development; Disease; Dose; Dose-Limiting; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Drug resistance; Enzyme Inhibition; Enzymes; Event; Extramedullary; Formulation; Future Generations; Goals; Half-Life; Hematology; Hepatic; Hepatotoxicity; Hyaluronic Acid; In Vitro; Lead; Length; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolic; Modeling; Molecular Weight; Morbidity - disease rate; Multiple Myeloma; Mus; Nervous System Physiology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Plasma Cells; Polymers; Positioning Attribute; Process; Prodrugs; Production; Property; Protein Geranylgeranylation; Protein Secretion; Proteins; Renal function; Structure; System; Tail; Therapeutic; Therapeutic Agents; Toxic effect; Toxicology; Translating; Triazoles; Veins; Vesicle; Xenograft Model; Xenograft procedure; analog; arm; base; bisphosphonate; clinically relevant; design; drug development; efficacy evaluation; efficacy testing; endoplasmic reticulum stress; farnesyltranstransferase; geranylgeranyl pyrophosphate; geranylgeranylation; heart function; improved; in vivo; in vivo evaluation; inhibitor/antagonist; isoprenoid; novel; novel strategies; novel therapeutic intervention; novel therapeutics; phosphonate; preclinical study; protein transport; response; stereochemistry; trafficking; tumor; uptake

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.

项目概要 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）。耐药性和脱靶效应的发展限制了目前的疗效 可用的代理。因此，迫切需要新的治疗策略，包括药物递送策略。 需要。我们重点关注通过抑制 MM 细胞中 MP 运输的新策略 香叶基香叶基二磷酸合酶 (GGDPS)。 GGDPS 抑制剂 (GGSI) 破坏 Rab 香叶基香叶基化，导致细胞内 MP 积累、内质网应激、所有三个臂的诱导 未折叠的蛋白质反应途径和最终 MM 细胞死亡。我们的 GGSI 开发工作已 专注于类异戊二烯三唑二膦酸盐，我们的结构功能研究已确定 类异戊二烯链长度和立体化学影响抑制剂效力以及体内生物分布。 我们的主要 GGSI 的临床前研究已经证明了关键的药物特性，包括代谢 稳定性、延长血浆半衰期、全身分布、体内蛋白质香叶基香叶基化的破坏和 小鼠 MM 异种移植模型中的抗肿瘤功效。剂量探索和毒理学研究表明肝脏 毒性为剂量限制，对血液、肾、心脏或神经功能没有影响。我们的初步 研究表明，改变透明质酸 (HA) 聚合物的分子量可以限制肝脏的摄取 并增强 BM 摄取，并且 MM 细胞很容易摄取 HA。因此我们假设治疗 通过将我们的 GGSI 与 HA 聚合物连接，可以优化 GGSI 的潜力，从而增强 GGSI 到 BM 并最大限度地减少肝脏摄取，我们的初步研究支持这一假设。对此 最后，我们将合成基于我们的先导化合物但在 α- 处进行修饰的新型 GGSI 允许与 HA 缀合或通过膦酸酯前药形式与 HA 连接的位置（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晶体学研究，以澄清 这些 GGSI 与目标酶相互作用的机制（目标 1），这将有助于设计 下一代 GGSI。我们将确定药代动力学/药效学特征和 新型可连接 GGSI 和相应的 HA 聚合物缀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。先导 GGSI-HA 的功效 将在模拟髓外和髓质疾病的异种移植研究中评估缀合物 参与（目标 3）。评估 GGSI 疗法与临床使用组合的体外和体内研究 将进行抗MM剂治疗。虽然我们目前的重点是开发 GGSI 疗法来治疗 MM， 这些研究具有更重要的意义，因为这种药物与 HA 结合的新方法可以改变 生物分布可应用于输送其他临床相关药物来治疗多发性骨髓瘤。