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：
10259368
负责人：
Donald Lo
金额：
$ 50.28万
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/10259368
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 Dana-Farber Cancer Institute Development Digit structure Dose Drug Kinetics Epidermal Growth Factor Epidermal Growth Factor Receptor FLT3 gene Formulation HDAC6 gene Histone Deacetylase Histone Deacetylase Inhibitor Human International Journals Lead Legal patent Link Literature Malignant Neoplasms 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 efficacy study improved in vivo inhibitor/antagonist kinase inhibitor lead optimization mutant nanomolar nanoparticle novel rare cancer scale up 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 scaled up the synthesis of TRND00507679 and submitted it to our collaborator at Dana-Farber Cancer Institute for an in vivo anti-AML efficacy study in mice. We have also completed development of the nano-particle formulation for TRND00507679 and TRND00421925 and studied their cellular uptake and anti-proliferative activity in several human cancer cell lines. Work to date has resulted in a publication in the Journal of Medicinal Chemistry and submission of an international patent application.

我们已经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单位纳摩尔效力的两个靶标。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诱导了来自AML患者的几种突变体和FLT3的AML细胞系和初级爆炸中的坏死。我们已经扩大了TRND00507679的合成，并将其提交给我们的Dana-Farber癌症研究所的合作者，用于小鼠体内抗AML疗效研究。我们还完成了TRND00507679和TRND00421925的纳米粒子制剂的开发，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。迄今为止的工作导致了《药化学杂志》的出版物和提交国际专利申请的出版物。