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：
Donald Lo
金额：
$ 85.3万
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/10686743
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 Employee Epidermal Growth Factor Epidermal Growth Factor Receptor FLT3 gene Formulation HDAC4 gene HDAC6 gene Histone Deacetylase Histone Deacetylase Inhibitor Human International Joints Journals Lead Legal patent Link Literature Malignant Neoplasms Methods Modeling Mus National Center for Advancing Translational Sciences Necrosis Pathway interactions Patients Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phosphatidylinositols Phosphotransferases Polymers Publications Publishing 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 invention kinase inhibitor lead optimization malignant breast neoplasm mutant nano nanoencapsulated nanomolar nanoparticle novel rare cancer synergism tumor tumor growth uptake

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.

以前，我们设计和合成了新型的双HDAC/PI3K抑制剂，鉴定了几个新型分子，这些分子抑制了两个具有单数纳摩尔效力的靶标。选定的化合物已在NCI60细胞系列面板中进行了测试，显示了几种细胞系中的抗增殖和细胞杀伤活性。这些子集在基于细胞的目标参与分析中进行了检查，证实了双重抑制剂在细胞中与PI3K-DELTA和HDAC6互动。铅化合物（TRND00507679）在AML患者的几种突变体和FLT3抗AML细胞系以及初级爆炸中诱导了坏死。我们已经开发了TRND00507679和TRND00421925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。 TRND00507679封装的纳米颗粒（TRND00507679-NP）在体内乳腺癌Ehrlich腹水肿瘤（EAT）模型中显示出剂量依赖性肿瘤生长的抑制作用。此外，我们还比较了由PI3K-DELTA抑制剂，基于Idelalisib的纳米粒子（Idelalisib-NP）与TRND0050507679-NP的肿瘤生长抑制作用。与idelalisib-NP相反，小鼠的饮食肿瘤的治疗与TRND00507679-NP的肿瘤生长大幅降低有关。所描述的工作发表在《药化学杂志》上。当前的努力导致了一项国际专利的题为：磷酸肌醇3-激酶和组蛋白脱乙酰基酶治疗癌症的抑制剂。此外，这些纳米成型的PI3K-DELTA/HDAC6双重抑制剂是通过最近提交的员工发明记录（EIR）标题为“：Polymeric nanoparticles构成了组合型脱脂酶6/phose”的纳米成型PI3K-DELTA/HDAC6双重抑制剂，启动了这些纳米成型的PI3K-DELTA/HDAC6双重抑制剂，从方法。