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：
10652443
负责人：
WEI LI
金额：
$ 53.07万
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/10652443
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 Disease Progression Down-Regulation Drug Design Drug Kinetics 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 Pharmacodynamics 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 cancer cell cancer drug resistance cancer therapy cancer type design efficacy study genome editing high throughput screening in vivo inhibitor leukemia meter 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生存蛋白。 MDM2 作为癌蛋白，促进癌症进展主要通过抑癌基因p53的抑制，而抗凋亡蛋白XIAP 通过抑制治疗诱导的细胞凋亡，在治疗耐药性的发展中发挥关键作用。 MDM2 已在多种人类癌症中检测到 XIAP 过度表达和上调，但在正常细胞中未检测到。细胞/组织，肿瘤细胞中 MDM2 和 XIAP 表达升高与疾病进展相关以及治疗效果不佳。我们之前的研究阐明了 MDM2 C 端 RING 结构域的分子机制与 XIAP IRES mRNA 相互作用，导致 MDM2 蛋白稳定并增强 XIAP 的翻译；这导致 MDM2 和 XIAP 的表达同时增加，从而促进癌症进展和耐药性。我们最近建立了一种荧光偏振 (FP) 测定法，用于高通量筛选 (HTS) 化学库并鉴定出与 MDM2 RING 结构域结合的化合物 (MX69) 并阻断或破坏其与 XIAP IRES mRNA 的相互作用。阻止这种相互作用会导致同时发生抑制 MDM2 和 XIAP，导致癌细胞凋亡和死亡。本提案的总体目标旨在开发一种基于 MX69 支架的潜在新型靶向药物，针对过度表达 MDM2 的肿瘤。如上所述，这些肿瘤通常还以 MDM2 依赖性方式上调 XIAP，从而导致增强耐药性。具体来说，我们将基于MX69结构进行计算机辅助药物设计，并迭代优化 MDM2 结合和抗癌活性（目标 1）。我们将定义分子和生物学通过解析 MDM2 的 X 射线晶体结构，了解新型 MX69 类似物的作用机制多种 MX69 类似物，以确认靶向 MDM2/XIAP 抑制并评估任何潜在的非特异性效果（目标 2）。我们将进行临床前研究来评估化合物稳定性、药代动力学 (PK) 和最佳 MX69 类似物的药效 (PD) 特性；使用以下方法评估其体内抗癌活性人类小鼠癌症模型；并确定对正常细胞/组织的任何潜在毒性（目标 3）。之上该项目完成后，我们将确定双靶向 MDM2/XIAP 作为新型药物的可行性治疗机制，并将开发出有前景的小分子抑制剂用于进一步的临床前研究评估不仅针对本提案中研究的白血病和神经母细胞瘤，而且还针对其他癌症类型。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Discovery of N-(3,4-Dimethylphenyl)-4-(4-isobutyrylphenyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline-8-sulfonamide as a Potent Dual MDM2/XIAP Inhibitor.

发现 N-(3,4-二甲基苯基)-4-(4-异丁酰苯基)-2,3,3a,4,5,9b-六氢呋喃[3,2-c]喹啉-8-磺酰胺作为有效的双 MDM2

DOI：
发表时间：
2021
期刊：
影响因子：
7.3
作者：
Wu, Zhongzhi;Gu, Lubing;Zhang, Sicheng;Liu, Tao;Lukka, Pradeep B;Meibohm, Bernd;Bollinger, John C;Zhou, Muxiang;Li, Wei
通讯作者：
Li, Wei

MYCN mRNA degradation and cancer suppression by a selective small-molecule inhibitor in MYCN-amplified neuroblastoma.

选择性小分子抑制剂在 MYCN 扩增神经母细胞瘤中的 MYCN mRNA 降解和癌症抑制作用。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Liu, Tao;Gu, Lubing;Wu, Zhongzhi;Albadari, Najah;Li, Wei;Zhou, Muxiang
通讯作者：
Zhou, Muxiang

Deciphering treatment resistance in metastatic colorectal cancer: roles of drug transports, EGFR mutations, and HGF/c-MET signaling.

解读转移性结直肠癌的治疗耐药性：药物转运、EGFR 突变和 HGF/c-MET 信号传导的作用。

DOI：
发表时间：
2023
期刊：
影响因子：
0
作者：
Albadari, Najah;Xie, Yang;Li, Wei
通讯作者：
Li, Wei

Design, Synthesis, and Biological Evaluation of Pyrimidine Dihydroquinoxalinone Derivatives as Tubulin Colchicine Site-Binding Agents That Displayed Potent Anticancer Activity Both In Vitro and In Vivo.

作为微管蛋白秋水仙碱位点结合剂的嘧啶二氢喹喔啉酮衍生物的设计、合成和生物学评价在体外和体内均表现出有效的抗癌活性。

DOI：
10.1021/acsptsci.2c00108
发表时间：
2023-03-22
期刊：
ACS pharmacology & translational science
影响因子：
0
作者：
Satyanarayana Pochampally;Kelli L. Hartman;Rui Wang;Jiaxing Wang;M. Yun;Keyur Parmar;Hyunseo Park
通讯作者：
Hyunseo Park

Molecular interactions at the colchicine binding site in tubulin: An X-ray crystallography perspective.

微管蛋白中秋水仙碱结合位点的分子相互作用：X 射线晶体学视角。