权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
Donald Lo
金额：
$ 107.1万
依托单位：
NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
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：
https://reporter.nih.gov/project-details/10470638
关键词：
1-Phosphatidylinositol 3-Kinase Address Apoptosis Biological Assay Cancer cell line Cell Cycle Cell Cycle Arrest Cell Line Cell Proliferation Cells Collaborations Cyclin D1 Development Digit structure Dose Drug Kinetics Ehrlich Tumor Carcinoma Epidermal Growth Factor Epidermal Growth Factor Receptor FLT3 gene Formulation HDAC6 gene Histone Deacetylase Histone Deacetylase Inhibitor Human International Joints Journals Lead Legal patent Link Literature Malignant Neoplasms Modeling Mus Necrosis Pathway interactions Patients Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phosphotransferases Publications Receptor Protein-Tyrosine Kinases Reporting Resistance Resistance development Signal Transduction Technology Testing Therapeutic Toxic effect Translating Tumor Suppressor Proteins Tyrosine Kinase Inhibitor Up-Regulation Work angiogenesis base c-myc Genes cancer initiation cancer therapy cell killing design improved in vivo inhibitor/antagonist kinase inhibitor lead optimization malignant breast neoplasm mutant nano nanoencapsulated nanomolar nanoparticle novel rare cancer synergism tumor tumor growth uptake

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。