Structure Based Design of Pol-theta inhibitors
Pol-theta 抑制剂的基于结构的设计
基本信息
- 批准号:10323627
- 负责人:
- 金额:$ 38.59万
- 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:2021-07-16 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAcute Myelocytic LeukemiaAcute leukemiaAdultBRCA deficientBinding ProteinsBiochemicalBiological AssayCellsClinicalCollaborationsCombined Modality TherapyComplexCrystallizationDNADNA DamageDNA RepairDNA Repair EnzymesDNA Repair InhibitionDNA-Directed DNA PolymeraseDataDiagnosisDisease remissionDouble Strand Break RepairDrug KineticsExperimental LeukemiaFLT3 geneGeneticGenetic RecombinationGoalsIn VitroLaboratoriesLeadLeukemic CellLiver MicrosomesMediatingMethodsMusMutationNormal CellPathway interactionsPatientsPharmaceutical ChemistryPharmaceutical PreparationsPhasePolymerasePropertyProteinsRUNX3 geneResolutionSolubilityStem cell transplantStructureStructure-Activity RelationshipTherapeuticTyrosine Kinase InhibitorX-Ray Crystallographyacute myeloid leukemia cellbasebrca genechemotherapydeoxyribonucleoside triphosphatedesigndrug candidatedrug developmenthigh throughput screeninghomologous recombinationin vivoin vivo Modelinhibitor/antagonistleukemiananomolarnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticspatient subsetspersonalized therapeuticphase 1 studyphase 2 studyprecision oncologyreceptorresponsesmall moleculestandard of caresuccesstargeted treatment
项目摘要
Acute myeloid leukemia (AML) is the most frequently diagnosed form of acute leukemia in adults, and standard
of care treatment involving chemotherapy and/or stem cell transplantation only cures 30-40% of patients. Recent
studies show that AMLs with FLT3 receptor activating internal tandem duplication (ITD) mutations (FLT3(ITD)-
positive AMLs) become defective in the BRCA1/2 pathway of homologous recombination (HR) following
treatment with tyrosine kinase inhibitors (TKi). BRCA-deficiency confers strong sensitivity to DNA damage and/or
DNA repair inhibition, and thus presents a promising new therapeutic strategy for AML. We discovered that
BRCA-deficient leukemia cells are hyper-dependent on the DNA repair enzyme DNA polymerase theta
(Polθ), which is dispensable for normal cells and mice. Polθ is involved in translesion synthesis and the
microhomology-mediated end-joining (MMEJ) double-strand break (DSB) repair pathway. Our leading small-
molecule Polθ inhibitor (Polθi) kills AML patient cells co-treated with the TKi quizartinib which causes
BRCA-deficiency, whereas quizartinib and Polθi as single agents shows significantly less killing. These
data demonstrate the Polθi + TKi combination as a promising therapeutic strategy for FLT3(ITD)-positive AML.
Polθi also shows preferential killing of other BRCA-deficient leukemias (ALL, CML) in vitro and in vivo, especially
in combination with TKi. In summary, our data discover Polθ as a novel drug target in leukemia, and demonstrate
Polθi + TKi as a promising therapeutic strategy, especially in aggressive FLT3(ITD)-positive AML. In phase I,
Recombination Therapeutics, LLC (RTx), a start-up precision oncology company, plans to increase the potency
of our leading Polθi as a novel treatment for FLT3(IDT)-positive AML using X-ray crystallography and structure
based optimization/design by developing the following Aims: 1. To solve the co-crystal structure of Polθ-DNA-
Polθi ternary complexes; 2. To optimize Polθi using structure based optimization/design.
In Phase II, RTx aims to achieve the following goals: 1. Further develop our leading Polθi drug candidate
by achieving more favorable ADME and pharmacokinetic parameters; 2. Characterize optimized Polθi in
combination with TKi in FLT3(IDT)-positive AML animal models in vivo.
急性髓性白血病(AML)是成人急性白血病最常见的诊断形式,也是标准的
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 }}
Richard T Pomerantz其他文献
Richard T Pomerantz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('Richard T Pomerantz', 18)}}的其他基金
Next-generation precision medicine for targeting recombination-deficient cancers
针对重组缺陷癌症的下一代精准医学
- 批准号:
9909705 - 财政年份:2020
- 资助金额:
$ 38.59万 - 项目类别:
PolQ as a novel therapeutic target in AML
PolQ 作为 AML 的新型治疗靶点
- 批准号:
10545175 - 财政年份:2020
- 资助金额:
$ 38.59万 - 项目类别:
PolQ as a novel therapeutic target in AML
PolQ 作为 AML 的新型治疗靶点
- 批准号:
10322361 - 财政年份:2020
- 资助金额:
$ 38.59万 - 项目类别:
Structure and Function of DNA Polymerase Theta
DNA 聚合酶 Theta 的结构和功能
- 批准号:
10094002 - 财政年份:2019
- 资助金额:
$ 38.59万 - 项目类别:
Structure and Function of DNA Polymerase Theta
DNA 聚合酶 Theta 的结构和功能
- 批准号:
10377900 - 财政年份:2019
- 资助金额:
$ 38.59万 - 项目类别:
Structure and Function of DNA Polymerase Theta
DNA 聚合酶 Theta 的结构和功能
- 批准号:
10336827 - 财政年份:2019
- 资助金额:
$ 38.59万 - 项目类别:
Mechanisms of Mammalian Double-Strand Break Repair
哺乳动物双链断裂修复机制
- 批准号:
9109640 - 财政年份:2015
- 资助金额:
$ 38.59万 - 项目类别:
相似海外基金
Computing analysis of leukemic stem cell dynamics in acute myelocytic leukemia
急性粒细胞白血病白血病干细胞动力学的计算分析
- 批准号:
19K08356 - 财政年份:2019
- 资助金额:
$ 38.59万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Generation of immunotoxins with super-targeting mAb in the acute myelocytic leukemia
在急性髓细胞白血病中使用超靶向单克隆抗体产生免疫毒素
- 批准号:
23501309 - 财政年份:2011
- 资助金额:
$ 38.59万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
DETERMINANTS OF RESPONSE OF ACUTE MYELOCYTIC LEUKEMIA
急性粒细胞白血病反应的决定因素
- 批准号:
3556971 - 财政年份:1980
- 资助金额:
$ 38.59万 - 项目类别:
DETERMINANTS OF RESPONSE OF ACUTE MYELOCYTIC LEUKEMIA
急性粒细胞白血病反应的决定因素
- 批准号:
3556968 - 财政年份:1980
- 资助金额:
$ 38.59万 - 项目类别:
ERADICATION OF ACUTE MYELOCYTIC LEUKEMIA CELLS BY MAB THERAPY
通过 MAB 疗法根除急性粒细胞白血病细胞
- 批准号:
3889304 - 财政年份:
- 资助金额:
$ 38.59万 - 项目类别:














{{item.name}}会员




