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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.

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。