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UPR Activators for Cancer Therapy

用于癌症治疗的 UPR 激活剂

基本信息

批准号：
10544342
负责人：
Amarnath Natarajan
金额：
$ 34.41万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10544342
关键词：
Acidosis Alkynes Antineoplastic Agents Apoptosis Avidin Azides Binding Biotin Ca(2+)-Transporting ATPase Calcium Cancer Model Cancer cell line Cells Chemicals Chemistry Clinical Cysteine Cytoplasm Development Endoplasmic Reticulum Evaluation Failure Foundations Goals Growth Hematologic Neoplasms In Situ Induction of Apoptosis Isatin Libraries Malignant Neoplasms Malignant neoplasm of ovary Mediating Mitochondria Modality Modification Normal Cell Nuclear Oncogenes Patients Pharmacodynamics Process Proteasome Inhibitor Proteins Proteome Reporting Sarcoplasm Signal Transduction Solid Neoplasm Stress Structure-Activity Relationship Surface Testing Thapsigargin Therapeutic Toxic effect Translating Tumor Suppressor Genes Tumor Suppressor Proteins Ubiquitinated Protein Degradation Up-Regulation Velcade Xenograft Model analog cancer cell cancer therapy crosslink design dimer efficacy evaluation endoplasmic reticulum stress experience imaging study improved in vivo in vivo Model inhibitor live cell imaging misfolded protein novel novel therapeutics nutrient deprivation oncogene addiction ovarian neoplasm pancreatic cancer model programs protein crosslink proteostasis response small molecule stressor success synergism trafficking tumor growth

项目摘要

Project Summary / Abstract The major goal in this application is to evaluate isatin-derived spirocyclic dimers as novel unfolded protein response (UPR) activators in proof-of-concept studies. Despite the dynamic changes in protein levels, protein homeostasis is maintained by a combination of tightly controlled processes which include synthesis, folding, trafficking and degradation. Accumulation of unfolded / misfolded proteins in the ER due to cell intrinsic and / or extrinsic signals results in the activation of UPR, an adaptation mechanism. Failure to resolve this results in irremediable ER stress and triggers UPR mediated programmed cell death. Cell intrinsic situations in cancer such as loss of tumor suppressor gene or oncogene addication result in higher basal UPR levels. Cancer cells maintain the higher basal UPR levels through upregulation of UPR associated proteins. The higher basal UPR levels in cancer cells provides a therapeutic window that can be exploited by UPR activators. This has been attributed to the success of proteasome inhibitors in the treatment of hematological malignancies. Although the success of proteasome inhibitors validates activation of UPR as a therapeutic modality, the need for UPR activators with novel mechanisms of action (MOA) is exemplified by the failure of proteasome inhibitors in patients with solid tumors. In this application we will address the above need by focusing on the development of a UPR activator with a novel MOA. We have identified an isatin-derived spirocyclic dimer (n7) that activates UPR in both normal and cancer cells but selectively induces apoptosis in cancer cells. Here we propose to continue the development of the novel chemical entity n7 through the following specific aims. Aim 1 will focus on characterization of n7 MOA, aim 2 will focus on structure activity relationship through synthesis and evaluation of n7 analogs and aim 3 will assess the efficacy of n7 or an improved UPR activator in in vivo models. Successful completion of the proposed aims will provide critical proof-of-concept for translating isatin-derived spirocyclic dimers as UPR activators.

项目摘要/摘要这一应用的主要目的是评价来自isatin的螺环二聚体是否为新的未折叠的。概念验证研究中的蛋白质反应(UPR)激活剂。尽管蛋白质水平有动态变化，蛋白质的动态平衡是通过一系列严格控制的过程来维持的，其中包括合成、折叠、贩运和退化。由于细胞固有的原因，未折叠/错误折叠蛋白在内质网中的积累和/或外部信号导致UPR的激活，UPR是一种适应机制。未能解决此问题导致不可修复的内质网应激，并触发UPR介导的程序性细胞死亡。中的单元格内部情况癌症，如抑癌基因缺失或癌基因添加，会导致基础UPR水平升高。癌细胞通过上调UPR相关蛋白来维持较高的基础UPR水平。这个癌细胞中较高的基础UPR水平提供了一个可被UPR激活剂利用的治疗窗口。这归功于蛋白酶体抑制剂在治疗血液病方面的成功。恶性肿瘤。尽管蛋白酶体抑制剂的成功证实了UPR的激活是一种治疗作为一种方式，对具有新的作用机制(MOA)的普遍定期审议激活剂的需求的例证是实体瘤患者中的蛋白酶体抑制剂。在本应用程序中，我们将通过以下方式满足上述需求重点开发了一种具有新型MOA的UPR激活剂。我们已经鉴定出一种从板蓝素中提取的螺旋二聚体(N7)，激活正常细胞和癌细胞中的UPR，但选择性地诱导细胞凋亡癌细胞。在这里，我们建议继续开发新的化学实体N7通过遵循特定的目标。目标1将侧重于N7 MOA的特征，目标2将侧重于结构活性通过合成和评估N7类似物与Aim 3的关系将评估N7或An的疗效改进的体内模型中的UPR激活剂。成功完成拟议的目标将提供关键的将靛红衍生的螺环二聚体翻译为UPR激活剂的概念验证。