HDAC/PI3K Dual Inhibitors for Treatment of Rare Cancers
HDAC/PI3K 双重抑制剂治疗罕见癌症
基本信息
- 批准号:10470638
- 负责人:
- 金额:$ 107.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAddressApoptosisBiological AssayCancer cell lineCell CycleCell Cycle ArrestCell LineCell ProliferationCellsCollaborationsCyclin D1DevelopmentDigit structureDoseDrug KineticsEhrlich Tumor CarcinomaEpidermal Growth FactorEpidermal Growth Factor ReceptorFLT3 geneFormulationHDAC6 geneHistone DeacetylaseHistone Deacetylase InhibitorHumanInternationalJointsJournalsLeadLegal patentLinkLiteratureMalignant NeoplasmsModelingMusNecrosisPathway interactionsPatientsPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPhosphotransferasesPublicationsReceptor Protein-Tyrosine KinasesReportingResistanceResistance developmentSignal TransductionTechnologyTestingTherapeuticToxic effectTranslatingTumor Suppressor ProteinsTyrosine Kinase InhibitorUp-RegulationWorkangiogenesisbasec-myc Genescancer initiationcancer therapycell killingdesignimprovedin vivoinhibitor/antagonistkinase inhibitorlead optimizationmalignant breast neoplasmmutantnanonanoencapsulatednanomolarnanoparticlenovelrare cancersynergismtumortumor growthuptake
项目摘要
We have designed and synthesized novel dual HDAC/PI3K inhibitors, identifying several novel molecules that inhibit both targets with single digit nanomolar potency. Selected compounds have been tested in the NCI60 cell line panel, showing anti-proliferation and cell-killing activity in several cell lines. A subset of these were examined in cell-based target engagement assays, confirming that the dual inhibitors engage both PI3K-delta and HDAC6 in cells. The lead compound (TRND00507679) induced necrosis in several mutant and FLT3-resistant AML cell lines and primary blasts from AML patients. We have developed the nano-particle formulation for TRND00507679 and TRND00421925 and studied their cellular uptake and anti-proliferative activity in several human cancer cell lines. TRND00507679 encapsulated nano-particles (TRND00507679-NPs) displayed a dose-dependent inhibition of tumor growth in an in vivo breast cancer Ehrlich ascites tumor (EAT) model. Additionally, we have also compared the tumor growth inhibition caused by PI3K-delta inhibitor, Idelalisib based nano-particles (Idelalisib-NPs) with that of TRND00507679-NPs. In contrast to Idelalisib-NPs, treatment of EAT tumors in mice was associated with substantial reduction in tumor growth by TRND00507679-NPs.
Work to date has resulted in a publication in the Journal of Medicinal Chemistry and submission of an international patent application. Additionally, filing of a joint inventorship patent between Hillstream Biopharma, Inc. and NCATS for these nano-formulated PI3Kdelta-HDAC6 dual inhibitors is currently underway.
我们已经设计并合成了新型的双重HDAC/PI 3 K抑制剂,鉴定了几种新型分子,其以个位数纳摩尔效力抑制两种靶标。已在NCI 60细胞系组中测试了选定的化合物,在几种细胞系中显示出抗增殖和细胞杀伤活性。在基于细胞的靶标接合测定中检查了其中的一个子集,证实了双重抑制剂在细胞中接合PI 3 K-δ和HDAC 6。先导化合物(TRND 00507679)在几种突变型和FLT 3耐药AML细胞系和AML患者的原代母细胞中诱导坏死。我们已经开发了TRND 00507679和TRND 00421925的纳米颗粒制剂,并研究了它们在几种人类癌细胞系中的细胞摄取和抗增殖活性。TRND 00507679包封的纳米颗粒(TRND 00507679-NP)在体内乳腺癌埃利希腹水肿瘤(EAT)模型中显示出对肿瘤生长的剂量依赖性抑制。此外,我们还比较了由PI 3 K-δ抑制剂、基于Idelalisib的纳米颗粒(Idelalisib-NP)与TRND 00507679-NP引起的肿瘤生长抑制。 与Idelalisib-NP相反,小鼠中EAT肿瘤的治疗与TRND 00507679-NP显著降低肿瘤生长相关。
迄今为止的工作成果已在《药物化学杂志》上发表,并提交了一项国际专利申请。此外,Hillstream Bioburma,Inc.和NCATS这些纳米配方PI 3 Kdelta-HDAC 6双重抑制剂目前正在进行中。
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(1)
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Donald Lo其他文献
Donald Lo的其他文献
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{{ truncateString('Donald Lo', 18)}}的其他基金
Studies of Tumor-Penetrating Microparticles for Pancreatic Cancer
肿瘤穿透微粒治疗胰腺癌的研究
- 批准号:
10470633 - 财政年份:
- 资助金额:
$ 107.1万 - 项目类别:
Studies of Tumor-Penetrating Microparticles for Pancreatic Cancer
肿瘤穿透微粒治疗胰腺癌的研究
- 批准号:
10685882 - 财政年份:
- 资助金额:
$ 107.1万 - 项目类别:
Evaluation of ACT1 to Treat Diabetic Keratopathy
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10470634 - 财政年份:
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Helping to End Addiction Long-term (HEAL): Development of Clinical Candidate Drugs for Pain, Addiction and Overdose
帮助长期戒除成瘾 (HEAL):开发治疗疼痛、成瘾和药物过量的临床候选药物
- 批准号:
10686744 - 财政年份:
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$ 107.1万 - 项目类别:
COVID-19: Identification and Development of Clinical Candidates to Treat SARS-CoV-2
COVID-19:识别和开发治疗 SARS-CoV-2 的临床候选药物
- 批准号:
10686748 - 财政年份:
- 资助金额:
$ 107.1万 - 项目类别:
HDAC/PI3K Dual Inhibitors for Treatment of Rare Cancers
HDAC/PI3K 双重抑制剂治疗罕见癌症
- 批准号:
10259368 - 财政年份:
- 资助金额:
$ 107.1万 - 项目类别:
COVID-19: Identification and Development of Clinical Candidates to Treat SARS-CoV-2
COVID-19:识别和开发治疗 SARS-CoV-2 的临床候选药物
- 批准号:
10259371 - 财政年份:
- 资助金额:
$ 107.1万 - 项目类别:
HEAL: Development of Clinical Candidate Drugs for Pain, Addiction and Overdose
HEAL:开发治疗疼痛、成瘾和药物过量的临床候选药物
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10259369 - 财政年份:
- 资助金额:
$ 107.1万 - 项目类别:
Development of Nogo Receptor Decoy for the Treatment of Spinal Cord Injury
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10686732 - 财政年份:
- 资助金额:
$ 107.1万 - 项目类别:
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