Chemical disruption of Wnt-mediated signal transduction

Wnt 介导的信号转导的化学破坏

基本信息

批准号：
8506757
负责人：
LAWRENCE LUM
金额：
$ 46.4万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8506757
关键词：
Acylation Acyltransferase Adult Affect Anabolism Anti-Obesity Agents Antineoplastic Agents Basal Cell Binding Biology Breast Melanoma Bypass Cancer cell line Cancerous Cell Differentiation process Cells Chemicals Clinical Coenzyme A Cultured Cells Decision Making Dependence Development Disease Diving Drug Targeting Effectiveness Embryonic Development Enzymatic Biochemistry Enzymes Family Family member Fatty Acids Gene Family Genes Genetic Human Individual Investments Ligands Lung Malignant Neoplasms Malignant neoplasm of lung Mediating Membrane Modeling Molecular Molecular Genetics Monounsaturated Fatty Acids Mus Pathway interactions Patients Phase Population Porcupines Process Production Protein Family Regulation Resistance Role Serine Shapes Signal Transduction Signaling Molecule Signaling Protein Stearoyl-CoA Desaturase Stem cells Surveys T-cell acute lymphocytic leukemia 1 protein Testing Tissues Tumor Suppressor Proteins Wnt proteins adduct adult stem cell base cancer initiation cancer stem cell cell growth computerized data processing deviant fatty acylation improved in vivo inhibitor/antagonist malignant breast neoplasm member novel palmitoleic acid public health relevance research clinical testing response screening self-renewal small molecule small molecule libraries therapeutic target tool tumor tumor growth tumor initiation tumor progression

项目摘要

DESCRIPTION (provided by applicant): The cellular responses controlled by the secreted Wnt proteins are essential to almost all aspects of embryogenesis. In developed tissue, genetic and molecular alterations that give rise to misactivation of these signaling processes frequently drive cancerous cell growth. We have identified two distinct chemical strategies to disable Wnt-mediated signaling from screening a large synthetic chemical library in cultured cells. Whereas one compound class targets an acyltransferase essential for the production of Wnt molecules, another class promotes the destruction of a linchpin transcriptional co- activator. The cell growth inhibitory effect of disabling Wnt-mediated signaling in certain cancerous contexts is well established. Yet, the ability of chemically based strategies to achieve similar effects is largely untested. The studies in this proposal will interrogate Wnt-mediated signaling at the molecular, cellular, and organismal level using new chemical biology-based tools, and establish a framework for the deployment of Wnt inhibitors in cancerous contexts. In particular, we focus on lung cancer given the dependence of this disease on both targets of our compound portfolio. These studies should facilitate a transition from front-line anti-cancer agents that are generally toxic to rapidly diving cells to those that are tailored to the underlying genetics of individual cancers.

描述（由申请人提供）：由分泌的Wnt蛋白控制的细胞反应对于胚胎发生的几乎所有方面都是必不可少的。在发达的组织中，导致这些信号过程误导的遗传和分子改变经常促进癌细胞的生长。我们已经确定了两种不同的化学策略，可以禁用Wnt介导的信号传导，以免筛选培养细胞中的大型合成化学文库。而一个化合物类别靶向生产Wnt分子必不可少的酰基转移酶，而另一个类促进了linchpin转录共激活剂的破坏。细胞生长在某些癌性环境中禁用WNT介导的信号传导的抑制作用已得到很好的确定。然而，基于化学的策略实现相似效果的能力在很大程度上未经测试。该提案中的研究将使用新的基于化学生物学的工具在分子，细胞和生物水平上询问WNT介导的信号传导，并为在癌性环境中部署Wnt抑制剂建立框架。特别是，考虑到该疾病对我们化合物组合的两个靶标的依赖性，我们将重点放在肺癌上。这些研究应促进从一般对快速潜水细胞有毒的前线抗癌药物过渡到针对单个癌症基础遗传学量身定制的细胞的过渡。