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

基本信息

  • 批准号:
    10364685
  • 负责人:
  • 金额:
    $ 49.27万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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,其特征在于产生 蛋白单克隆(MP)。耐药性和脱靶效应的发展限制了目前药物治疗的疗效。 可用的代理人。因此,迫切需要新的治疗策略,包括药物递送策略, needed.我们已经集中在新的战略,针对贩运的MP在MM细胞通过抑制 酶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,其导致细胞内MP积累、ER应激、所有三个臂的诱导, 未折叠蛋白反应途径和最终MM细胞死亡。我们的GGSI开发工作 专注于类异戊二烯三唑双膦酸酯,我们的结构-功能研究已经确定, 类异戊二烯链长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样特性,包括代谢 稳定性、延长的血浆半衰期、全身分布、蛋白质香叶基香叶基化的体内破坏和 在小鼠MM异种移植模型中的抗肿瘤功效。剂量探索和毒理学研究显示, 毒性为剂量限制性,对血液学、肾脏、心脏或神经功能无影响。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摄取 并增强BM摄取,MM细胞易于摄取HA。因此,我们假设, GGSI的潜力可以通过我们的GGSI与HA聚合物的连接来优化,从而增强 GGSI的BM和最小化肝摄取,我们的初步研究支持这一假设。本 最后,我们将合成新的GGSI,它们是基于我们的先导化合物,但在α- 位置以允许缀合至HA或通过膦酸酯前药形式连接至HA(目的1) 详细的结构研究,包括结合抑制剂的蛋白质晶体学研究,以阐明 这些GGSI与靶酶(Aim 1)相互作用的机制,这将有助于设计 未来的几代人。我们将确定药代动力学/药效学特征, 新的HA GGSI和相应的HA聚合物缀合物的生物分布模式(目的2)。我们 将研究GGSI肝脏摄取和毒性的调节机制。电极导线GGSI-HA的有效性 将在模拟髓外和髓内疾病的异种移植物研究中评估缀合物 参与(目标3)。体外和体内研究评价GGSI疗法与临床使用的 将使用抗MM药物。虽然我们目前的重点是开发用于治疗MM的GGSI疗法, 这些研究增加了重要性,因为这种将药物偶联到HA上的新方法, 生物分布可应用于递送用于治疗MM的其它临床相关药剂。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Sarah A Holstein其他文献

Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk
基于达雷妥尤单抗的四联疗法治疗符合移植资格的新诊断的具有高细胞遗传学风险的多发性骨髓瘤
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    12.8
  • 作者:
    Natalie S. Callander;R. Silbermann;Jonathan L. Kaufman;K. Godby;J. Laubach;T. Schmidt;Douglas W Sborov;E. Medvedova;B. Reeves;B. Dhakal;Cesar Rodriguez;S. Chhabra;A. Chari;S. Bal;Larry D. Anderson;B. Dholaria;N. Nathwani;P. Hari;Nina Shah;N. Bumma;Sarah A Holstein;Caitlin Costello;A. Jakubowiak;T. M. Wildes;R. Orlowski;K. Shain;Andrew J Cowan;H. Pei;A. Cortoos;Sharmila Patel;Thomas S. Lin;Smith Giri;Luciano J Costa;Saad Z Usmani;Paul G Richardson;P. Voorhees
  • 通讯作者:
    P. Voorhees

Sarah A Holstein的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Sarah A Holstein', 18)}}的其他基金

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:
    10600005
  • 财政年份:
    2021
  • 资助金额:
    $ 49.27万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 49.27万
  • 项目类别:
Pilot Projects Program
试点项目计划
  • 批准号:
    10281660
  • 财政年份:
    2016
  • 资助金额:
    $ 49.27万
  • 项目类别:
Pilot Projects Program
试点项目计划
  • 批准号:
    10478961
  • 财政年份:
    2016
  • 资助金额:
    $ 49.27万
  • 项目类别:
Rab Geranylgeranylation: a Novel Therapeutic Target in Multiple Myeloma
Rab 香叶基香叶基化:多发性骨髓瘤的新治疗靶点
  • 批准号:
    9331012
  • 财政年份:
    2013
  • 资助金额:
    $ 49.27万
  • 项目类别:
Rab Geranylgeranylation: a Novel Therapeutic Target in Multiple Myeloma
Rab 香叶基香叶基化:多发性骨髓瘤的新治疗靶点
  • 批准号:
    8988538
  • 财政年份:
    2013
  • 资助金额:
    $ 49.27万
  • 项目类别:
Rab Geranylgeranylation: a Novel Therapeutic Target in Multiple Myeloma
Rab 香叶基香叶基化:多发性骨髓瘤的新治疗靶点
  • 批准号:
    8416249
  • 财政年份:
    2013
  • 资助金额:
    $ 49.27万
  • 项目类别:
Rab Geranylgeranylation: a Novel Therapeutic Target in Multiple Myeloma
Rab 香叶基香叶基化:多发性骨髓瘤的新治疗靶点
  • 批准号:
    8600246
  • 财政年份:
    2013
  • 资助金额:
    $ 49.27万
  • 项目类别:
Targets, Modulators and Delivery Program
靶标、调节剂和交付计划
  • 批准号:
    10270904
  • 财政年份:
    1997
  • 资助金额:
    $ 49.27万
  • 项目类别:
Targets, Modulators and Delivery Program
靶标、调节剂和交付计划
  • 批准号:
    10491749
  • 财政年份:
    1997
  • 资助金额:
    $ 49.27万
  • 项目类别:

相似海外基金

Real-time Disambiguation of Abbreviations in Clinical Notes
临床记录中缩写词的实时消歧
  • 批准号:
    8077875
  • 财政年份:
    2010
  • 资助金额:
    $ 49.27万
  • 项目类别:
Real-time Disambiguation of Abbreviations in Clinical Notes
临床记录中缩写词的实时消歧
  • 批准号:
    7866149
  • 财政年份:
    2010
  • 资助金额:
    $ 49.27万
  • 项目类别:
Real-time Disambiguation of Abbreviations in Clinical Notes
临床记录中缩写词的实时消歧
  • 批准号:
    8589822
  • 财政年份:
    2010
  • 资助金额:
    $ 49.27万
  • 项目类别:
Real-time Disambiguation of Abbreviations in Clinical Notes
临床记录中缩写词的实时消歧
  • 批准号:
    8305149
  • 财政年份:
    2010
  • 资助金额:
    $ 49.27万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了