Molecular brush-conjugated antisense oligonucleotide as a pan-KRAS depletion agent
分子刷偶联反义寡核苷酸作为泛 KRAS 耗竭剂
基本信息
- 批准号:10771051
- 负责人:
- 金额:$ 5.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAnimal ModelAntisense OligonucleotidesAutomobile DrivingCellsClinicDrug KineticsGoalsHumanKRAS2 geneLungMalignant Epithelial CellMalignant NeoplasmsMarketingMethodsModalityMolecularMonkeysMusMutateMutationNucleic AcidsOncogenesOncoproteinsPharmaceutical PreparationsPharmacology StudyPharmacology and ToxicologyPhasePlasmaProteinsRefractoryResearchStructureTechnologyTherapeutic AgentsTherapeutic InterventionTranslatingXenograft Modeldosageimprovedin vivoinhibitormouse modelmutantnonhuman primatenovelnucleic acid-based therapeuticspatient derived xenograft modelpharmacologicpre-clinicalside effectsmall moleculetumoruptake
项目摘要
Project Summary/Abstract
Mutant forms of KRAS are a key driver in human tumors but remain partially refractory to therapeutic
intervention. After over three decades of research, only a single inhibitor (sotorasib) targeting a single
mutation (KRASG12C) have reached market. The difficulty for developing small molecule KRAS inhibitors
has heightened the importance of alternative methods targeting the oncogene. One such strategy
involves therapeutic nucleic acids, which make it possible to deplete target proteins that are intractable to
conventional drug modalities. We have developed a novel form of nucleic acid therapeutics, termed
Brushield™ conjugate, which substantially enhances the antitumor activity of antisense oligonucleotides
by elevating in vivo stability, accelerating cellular uptake, and improving plasma pharmacokinetics and
tumor accumulation, allowing for a much lower dosage to be used compared to conventional methods.
The conjugate also suppresses nearly all side effects associated with traditional nucleic acid drugs by
reducing unwanted nucleic acid-protein interactions. The goal of this proposal is to lay the groundwork
for translating the technology towards the clinic. In Phase I, we will optimize the structure of the
Brushield™ conjugate, and enhance current indication using a panel of non-small cell lung cells and
mouse xenograft models. Upon reaching set quantitative milestones, we will subject the conjugate to
more relevant animal models (orthotopic and patient-derived xenograft models), and perform tolerability
and pharmacokinetic studies in mice and monkeys (Phase II). These studies will allow us to pursue an
IND filing at the end of the project.
项目总结/摘要
KRAS的突变形式是人类肿瘤的关键驱动因素,但仍然部分难治性治疗。
干预经过三十多年的研究,只有一种针对单一靶点的抑制剂(sotorasib),
突变(KRASG 12 C)已进入市场。开发小分子KRAS抑制剂的困难
这也增加了针对致癌基因的替代方法的重要性。一种这样的策略
涉及治疗性核酸,这使得有可能耗尽难以治疗的靶蛋白。
传统的药物模式。我们已经开发了一种新形式的核酸疗法,称为
基本上增强反义寡核苷酸的抗肿瘤活性
通过提高体内稳定性、加速细胞摄取和改善血浆药代动力学,
肿瘤积聚,与常规方法相比,允许使用低得多的剂量。
所述缀合物还通过以下方式抑制与传统核酸药物相关的几乎所有副作用:
减少不需要的核酸-蛋白质相互作用。这项提议的目的是为
将这项技术应用于临床在第一阶段,我们将优化
使用一组非小细胞肺细胞,
小鼠异种移植模型。在达到设定的定量里程碑后,我们将使缀合物经受
更相关的动物模型(原位和患者来源的异种移植模型),并进行耐受性研究
以及小鼠和猴的药代动力学研究(II期)。这些研究将使我们能够寻求
在项目结束时提交IND。
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)
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Ke Zhang其他文献
Ke Zhang的其他文献
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{{ truncateString('Ke Zhang', 18)}}的其他基金
Development of a highly sensitive and specific POCT testing asthma triggering allergic IgE
开发高度敏感和特异的 POCT 测试哮喘触发过敏性 IgE
- 批准号:
10600767 - 财政年份:2023
- 资助金额:
$ 5.5万 - 项目类别:
Development of a highly sensitive and specific POCT testing asthma triggering allergic IgE
开发高度敏感和特异的 POCT 测试哮喘触发过敏性 IgE
- 批准号:
10817658 - 财政年份:2023
- 资助金额:
$ 5.5万 - 项目类别:
Molecular brush-conjugated antisense oligonucleotide as a pan-KRAS depletion agent
分子刷偶联反义寡核苷酸作为泛 KRAS 耗竭剂
- 批准号:
10544115 - 财政年份:2022
- 资助金额:
$ 5.5万 - 项目类别:
Molecular brush-conjugated antisense oligonucleotide as a pan-KRAS depletion agent
分子刷偶联反义寡核苷酸作为泛 KRAS 耗竭剂
- 批准号:
10896563 - 财政年份:2022
- 资助金额:
$ 5.5万 - 项目类别:
Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates
使用刷状结构的聚(乙二醇)-DNA 缀合物靶向致癌 KRAS
- 批准号:
10430047 - 财政年份:2020
- 资助金额:
$ 5.5万 - 项目类别:
Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates
使用刷状结构的聚(乙二醇)-DNA 缀合物靶向致癌 KRAS
- 批准号:
10653706 - 财政年份:2020
- 资助金额:
$ 5.5万 - 项目类别:
Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates
使用刷状结构的聚(乙二醇)-DNA 缀合物靶向致癌 KRAS
- 批准号:
10210369 - 财政年份:2020
- 资助金额:
$ 5.5万 - 项目类别:
Targeting Oncogenic KRAS with Brush-Architectured Poly(ethylene glycol)-DNA Conjugates
使用刷状结构的聚(乙二醇)-DNA 缀合物靶向致癌 KRAS
- 批准号:
10035113 - 财政年份:2020
- 资助金额:
$ 5.5万 - 项目类别:
Making Oligonucleotides Better Biopharmaceuticals by Steric Protection
通过空间保护使寡核苷酸成为更好的生物制药
- 批准号:
10659672 - 财政年份:2017
- 资助金额:
$ 5.5万 - 项目类别:
Making Oligonucleotides Better Biopharmaceuticals by Steric Protection
通过空间保护使寡核苷酸成为更好的生物制药
- 批准号:
10259829 - 财政年份:2017
- 资助金额:
$ 5.5万 - 项目类别:
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