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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.

项目总结/摘要本申请的主要目的是评价靛红衍生的螺环二聚体作为新的未折叠的蛋白质反应（UPR）激活剂的概念验证研究。尽管蛋白质水平发生了动态变化，蛋白质稳态通过严格控制的过程的组合来维持，折叠、运输和降解。由于细胞内分泌，未折叠/错误折叠蛋白在ER中积累和/或外部信号导致UPR（一种适应机制）的激活。未能解决这个问题导致不可补救的ER应激并触发UPR介导的程序性细胞死亡。细胞内在情况肿瘤如肿瘤抑制基因缺失或癌基因添加导致较高的基础UPR水平。癌细胞通过上调UPR相关蛋白质来维持较高的基础UPR水平。的癌细胞中较高的基础UPR水平提供了可被UPR激活剂利用的治疗窗口。这归因于蛋白酶体抑制剂在治疗血液病中的成功。恶性肿瘤虽然蛋白酶体抑制剂的成功验证了UPR作为治疗剂的激活模式，需要UPR激活剂与新的作用机制（MOA）的失败，蛋白酶体抑制剂在实体瘤患者中的应用。在本申请中，我们将通过以下方式解决上述需求：重点在于开发具有新型MOA的UPR活化剂。我们发现了一种靛红衍生物一种螺环二聚体（n7），在正常细胞和癌细胞中激活UPR，但在癌细胞中选择性诱导凋亡。癌细胞在此，我们建议通过以下方法继续开发新的化学实体n7：具体目标。目标1将侧重于n7 MOA的表征，目标2将侧重于结构活性通过N7类似物的合成和评价的关系和AIM 3将评估N7或AN的功效体内模型中改进的UPR激活剂。成功完成拟议目标将为用于翻译靛红衍生的螺环二聚体作为UPR活化剂的概念验证。