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:10686743
- 负责人:
- 金额:$ 85.3万
- 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 CarcinomaEmployeeEpidermal Growth FactorEpidermal Growth Factor ReceptorFLT3 geneFormulationHDAC4 geneHDAC6 geneHistone DeacetylaseHistone Deacetylase InhibitorHumanInternationalJointsJournalsLeadLegal patentLinkLiteratureMalignant NeoplasmsMethodsModelingMusNational Center for Advancing Translational SciencesNecrosisPathway interactionsPatientsPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPhosphatidylinositolsPhosphotransferasesPolymersPublicationsPublishingReceptor Protein-Tyrosine KinasesReportingResistanceResistance developmentSignal TransductionTechnologyTestingTherapeuticToxic effectTranslatingTumor Suppressor ProteinsTyrosine Kinase InhibitorUp-RegulationWorkangiogenesisbasec-myc Genescancer initiationcancer therapycell killingdesignimprovedin vivoinhibitorinventionkinase inhibitorlead optimizationmalignant breast neoplasmmutantnanonanoencapsulatednanomolarnanoparticlenovelrare cancersynergismtumortumor growthuptake
项目摘要
Previously we 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. The described work was published in the Journal of Medicinal Chemistry.
Current efforts have resulted in the publication of an international patent titled: Inhibitors of phosphoinositide 3-kinase and histone deacetylase for treatment of cancer. Additionally, filing of a joint inventorship patent between Hillstream Biopharma, Inc. and NCATS for these nano-formulated PI3K-delta/HDAC6 dual inhibitors was launched by recent submission of an Employee Invention Record (EIR) titled: Polymeric nanoparticles comprising a histone deacetylase 6/phosphoinositide 3-Kinase-delta dual inhibitor and related methods.
在此之前,我们设计并合成了新的双HDAC/PI3K抑制剂,鉴定了几个新的分子,它们以个位数的纳摩尔效力抑制这两个靶点。选定的化合物已经在NCI60细胞系面板中进行了测试,在几种细胞系中显示出抗增殖和细胞杀伤活性。在基于细胞的靶结合分析中检查了其中的一个子集,证实了双重抑制物在细胞中同时结合了PI3K-Delta和HDAC6。先导化合物(TRND00507679)导致几个突变的和耐Flt3的AML细胞系和AML患者的原代母细胞发生坏死。我们已经开发了TRND00507679和TRND00421925的纳米颗粒配方,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。TRND00507679包裹的纳米颗粒(TRND00507679-NPs)在体内乳腺癌Ehrlich腹水瘤(EAT)模型中显示出剂量依赖性的抑制肿瘤生长。此外,我们还比较了PI3K-Delta抑制剂Idelalisib纳米粒子(Idelalisib-NPs)和TRND00507679-NPs对肿瘤生长的抑制作用。与Idelalisib-NPs相比,治疗小鼠EAT肿瘤与TRND00507679-NPs显著减少肿瘤生长有关。这项研究发表在《药物化学杂志》上。
目前的努力已经导致发表了一项名为:用于治疗癌症的磷脂酰肌醇3-激酶和组蛋白脱乙酰酶的抑制剂的国际专利。此外,Hillstream Biophma,Inc.和NCATS对这些纳米配方的PI3K-Delta/HDAC6双重抑制剂的联合发明专利的申请是通过最近提交的一份员工发明记录(EIR)发起的,标题为:包含组蛋白脱乙酰基酶6/磷酸肌醇3-Kinase-Delta双重抑制剂的聚合物纳米颗粒和相关方法。
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 }}
Donald Lo其他文献
Donald Lo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('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:
$ 85.3万 - 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:
$ 85.3万 - 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:
10470638 - 财政年份:
- 资助金额:
$ 85.3万 - 项目类别:
Evaluation of ACT1 to Treat Diabetic Keratopathy
ACT1 治疗糖尿病角膜病的评价
- 批准号:
10470634 - 财政年份:
- 资助金额:
$ 85.3万 - 项目类别:
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:
- 资助金额:
$ 85.3万 - 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:
$ 85.3万 - 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:
$ 85.3万 - 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:
$ 85.3万 - 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
- 批准号:
10259369 - 财政年份:
- 资助金额:
$ 85.3万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 85.3万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 85.3万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 85.3万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 85.3万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 85.3万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 85.3万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 85.3万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 85.3万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 85.3万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 85.3万 - 项目类别:
Research Grant














{{item.name}}会员




