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Dual inhibition of MDM2 and XIAP as a therapeutic strategy in cancer

MDM2 和 XIAP 双重抑制作为癌症治疗策略

基本信息

批准号：
10224705
负责人：
WEI LI
金额：
$ 54.15万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-28 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10224705
关键词：
Antibodies Apoptosis Apoptotic BIRC4 gene Back Binding Biological Biological Assay Biotechnology C-terminal CRISPR/Cas technology Calorimetry Cell Line Cell Survival Cessation of life Clinical Complex Computer Assisted Crystallization Disease Progression Down-Regulation Drug Design Drug resistance Evaluation Fluorescence Polarization Genes Goals Human Immune Induction of Apoptosis Internal Ribosome Entry Site Knock-out Leukemic Cell MDM2 gene Malignant Neoplasms Measurement Messenger RNA Molecular Molecular Biology Mus Neuroblastoma Normal Cell Oncoproteins Pharmaceutical Chemistry Play Property Proteins Publishing Resistance development Roentgen Rays Role SCID Mice Structure Structure-Activity Relationship Surface Plasmon Resonance TP53 gene Testing Therapeutic Tissues Titrations Toxic effect Transfection Translations Treatment outcome analog anti-cancer anticancer activity anticancer treatment base cancer cell cancer drug resistance cancer therapy cancer type design efficacy study genome editing high throughput screening in vivo inhibitor/antagonist leukemia molecular modeling mouse model neoplastic cell neuroblastoma cell novel novel therapeutics overexpression pharmacokinetics and pharmacodynamics preclinical evaluation preclinical study scaffold small molecule inhibitor small molecule libraries structural biology targeted agent targeted treatment tumor tumor progression

项目摘要

MDM2 and XIAP are important cell-survival proteins in tumor cells. MDM2 acts as an oncoprotein, promoting cancer progression mainly through inhibition of the tumor suppressor p53, while the anti-apoptotic protein XIAP plays a critical role in development of resistance to treatment via inhibition of therapy-induced apoptosis. MDM2 overexpression and upregulated XIAP have been detected in various human cancers but not in normal cells/tissues, and elevated MDM2 and XIAP expression in tumor cells is associated with disease progression and poor treatment outcomes. Our previous studies elucidated a molecular mechanism by which the MDM2 C-terminal RING domain interacts with XIAP IRES mRNA resulting in stabilization of MDM2 protein and enhanced translation of XIAP; this led to concomitantly increased expression of both MDM2 and XIAP, contributing to cancer progression and drug resistance. We have recently established a fluorescence polarization (FP) assay for use in high-throughput screening (HTS) of chemical libraries and identified a compound (MX69) that binds to the MDM2 RING domain and blocks or disrupts its interaction with XIAP IRES mRNA. Blocking this interaction results in simultaneous inhibition of both MDM2 and XIAP, leading to cancer cell apoptosis and death. The overall goal of this proposal is to develop a potential novel targeted agent based on the MX69 scaffold against tumors overexpressing MDM2. As discussed above, these tumors also typically upregulate XIAP in an MDM2-dependent manner, resulting in enhanced drug resistance. Specifically, we will perform computer-aided drug design based on the MX69 structure and iteratively optimize MDM2 binding and anticancer activity (Aim 1). We will define the molecular and biological mechanism(s) of action of novel MX69 analogs by solving the X-ray crystal structures of MDM2 in complex with diverse MX69 analogs to confirm on-target MDM2/XIAP inhibition and to evaluate any potential nonspecific effects (Aim 2). We will perform preclinical studies to assess compound stability, pharmacokinetic (PK), and pharmacodynamic (PD) properties of the best MX69 analogs; to evaluate their anticancer activity in vivo using human cancer-in-mouse models; and to determine any potential toxicity to normal cells/tissues (Aim 3). Upon completion of this project, we will have determined the feasibility of dual targeting MDM2/XIAP as a novel therapeutic mechanism, and will have developed promising small molecule inhibitors for further preclinical evaluations, not only for leukemia and neuroblastoma as studied in this proposal, but also in other cancer types.

MDM2和XIAP是肿瘤细胞中重要的细胞存活蛋白。MDM2作为一种癌蛋白，促进