D-peptide activators of p53 as anticancer therapeutics

p53 的 D 肽激活剂作为抗癌疗法

基本信息

批准号：
8774207
负责人：
WUYUAN LU
金额：
$ 16.69万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8774207
关键词：
Affinity Animals Antineoplastic Agents Apoptotic Binding Biochemical Biological Biological Availability Breast Cancer Biology Cancer Patient Cancerous Cell Culture Techniques Cell Cycle Arrest Cell Membrane Permeability Cell membrane Cells Cellular Stress Chemicals Clinical Colon Carcinoma Complex DNA Binding Domain Development Experimental Designs Funding Genes Goals Growth Hand Health Homologous Gene Human Hydrocarbons Image Impairment In Vitro Induction of Apoptosis Laboratories Lead Left Ligands Liposomes Lung MDM2 gene Malignant Neoplasms Malignant neoplasm of liver Membrane Modification Molecular Molecular Conformation Molecular Target Mus Mutate N-terminal Normal Cell Oncogenic Parents Pathway interactions Peptide Hydrolases Peptides Phage Display Play Predisposition Property Protein Chemistry Protein p53 Proteins Proteolysis Reporting Research Resistance Role Series Side Signal Pathway Structure TP53 gene Techniques Testing Therapeutic Transactivation Tumor Cell Line Tumor Suppressor Proteins Uterine Cancer Xenograft Model analog anti-cancer therapeutic base biophysical techniques cancer therapy cell injury chemotherapy crosslink design drug discovery human disease in vivo inhibitor/antagonist innovation killings malignant stomach neoplasm neoplastic cell novel novel therapeutics nutlin 3 peptidomimetics prevent response structural biology synthetic peptide therapeutic target transcription factor tumor tumor growth tumorigenesis ubiquitin-protein ligase uptake weapons

项目摘要

DESCRIPTION (provided by applicant): The proposed multi-disciplinary research combines contemporary synthetic peptide/protein chemistry, structural biology, cancer biology, and various biochemical and biophysical techniques, showcasing a powerful, innovative, and integrated approach to filling an important gap in peptide-based anticancer drug discovery. If funded, this project will lead to the addition of new weapons to the existing anticancer arsenal, and broadly impact the development of peptide therapeutics for targeted molecular therapy of many other human diseases as well. Background: p53 is activated as a transcription factor to induce powerful growth inhibitory and apoptotic responses to cellular stress, but is otherwise tightly controlled in normal cells by its negative regulators MDM2 and MDMX. Impairment of the p53 pathway is a hallmark of almost all human tumors where either the TP53 gene is mutated or the p53 protein is functionally inactivated by MDM2 and MDMX. Over-expression or amplification of MDM2 and MDMX in many tumors correlates with a normal (wild type) status of p53, contributing to robust p53 inhibition and degradation. Recent studies have validated inhibition of the p53-MDM2/MDMX interaction as a new therapeutic paradigm for cancer treatment. Our laboratory has developed a series of high-affinity D- peptide antagonists of MDM2 and MDMX (DPMI-α,β,γ,δ) that, when delivered via a liposomal carrier vehicle, are capable of killing tumor cells in vitro and in vivo by activating the p53 pathway. Objective: Using DPMI-δ as a parent molecule (KD = 220 pM for MDM2 and 200 nM for MDMX), we seek to develop high-affinity, protease-resistant, and cell-penetrating D-peptide antagonists of MDM2 and MDMX for potential anticancer therapy. Specific Aims: (1) Design side-chain cross- linked forms of DPMI-δ capable of traversing the cell membrane to stabilize intracellular p53. We will use the hydrocarbon stapling technique to design a series of side-chain cross-linked analogs of DPMI- δ, and evaluate their functional and structural properties with respect to α-helicity, MDM2/MDMX binding, and membrane permeabilization. (2) Test the hypothesis that high-affinity, protease- resistant, and cell-penetrating D-peptide antagonists of MDM2 and MDMX reactivate the p53 pathway and kill tumor cells through cell cycle arrest and/or apoptosis induction. We will evaluate tumor-killing activity of side-chain cross-linked forms of DPMI-δ using a variety of tumor cell lines with or without wild type p53. Our long-term objective is to develop D-peptide-based p53 activators as a novel class of anticancer therapeutics for clinical use.

描述（由适用提供）：拟议的多学科研究结合了当代合成肽/蛋白质化学，结构生物学，癌症生物学以及各种生化和生物物理技术，展示了一种强大，创新的和综合的方法，可填补基于肽抗癌药物的重要缺口。如果资助，该项目将导致在现有的抗癌武器库中添加新武器，并广泛影响肽治疗的发展，以靶向许多其他人类疾病的靶向分子疗法。背景：p53被激活为转录因子，以诱导强大的生长抑制和对细胞应激的凋亡反应，但否则通过其负调节剂MDM2和MDMX在正常细胞中紧紧控制。 p53途径的损害是几乎所有人类肿瘤的标志，其中TP53基因被突变或p53蛋白在功能上被MDM2和MDMX灭活。许多肿瘤中MDM2和MDMX的过表达或扩增与p53的正常（野生型）状态相关，导致了强大的p53抑制和降解。最近的研究验证了对p53-MDM2/MDMX相互作用的抑制作用，作为用于癌症治疗的新治疗范式。我们的实验室已经开发了一系列MDM2和MDMX（DPMI-α，β，γ，δ）的高亲和力D肽拮抗剂，当通过脂质体载体载体传递时，可以通过激活P53途径来在体外和体内杀死肿瘤细胞。目的：使用DPMI-δ作为母体分子（MDM2的KD = 220 pm，MDMX为200 nm），我们试图开发MDM2和MDMX的高亲和力，抗蛋白酶耐药性和细胞穿透D肽拮抗剂，以实现潜在的抗癌治疗。具体目的：（1）设计侧链交联的dpmiΔ，能够遍历细胞膜以稳定细胞内p53。我们将使用碳氢化合物钉钉技术来设计一系列DPMI-δ的侧链交联类似物，并根据α-螺旋，MDM2/MDMX结合以及膜通透性评估其功能和结构特性。（2）检验以下假设：MDM2和MDMX的高亲和力，抗蛋白酶抗性和细胞渗透D肽拮抗剂可通过细胞周期停滞和/或凋亡诱导重新激活p53途径并杀死肿瘤细胞。我们将使用有或没有野生型p53的多种肿瘤细胞系评估DPMI-δ的侧链交联杀伤活性。我们的长期目标是开发基于D肽的p53激活剂，作为用于临床使用的新型抗癌治疗。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A stapled peptide antagonist of MDM2 carried by polymeric micelles sensitizes glioblastoma to temozolomide treatment through p53 activation.

DOI：
10.1016/j.jconrel.2015.09.061
发表时间：
2015-11-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
0
作者：
Chen X;Tai L;Gao J;Qian J;Zhang M;Li B;Xie C;Lu L;Lu W;Lu W
通讯作者：
Lu W

Peptide-Induced Self-Assembly of Therapeutics into a Well-Defined Nanoshell with Tumor-Triggered Shape and Charge Switch.

DOI：
10.1021/acs.chemmater.8b02572
发表时间：
2018
期刊：
Chemistry of materials : a publication of the American Chemical Society
影响因子：
0
作者：
He W;Yan J;Jiang W;Li S;Qu Y;Niu F;Yan Y;Sui F;Wang S;Zhou Y;Jin L;Li Y;Ji M;Ma PX;Liu M;Lu W;Hou P
通讯作者：
Hou P

Lanthanide-doped nanoparticles conjugated with an anti-CD33 antibody and a p53-activating peptide for acute myeloid leukemia therapy.