Chemical disruption of Wnt-mediated signal transduction

描述（由申请人提供）：由分泌的Wnt蛋白控制的细胞反应对胚胎发生的几乎所有方面都是必需的。在发达的组织中，导致这些信号传导过程误激活的遗传和分子改变经常驱动癌细胞生长。我们已经确定了两种不同的化学策略，以禁用Wnt介导的信号从筛选培养细胞中的大型合成化学文库。一类化合物靶向Wnt分子产生所必需的酰基转移酶，而另一类化合物促进关键转录共激活因子的破坏。细胞生长 在某些癌性环境中使Wnt介导的信号传导失能的抑制作用已被充分确立。然而，基于化学的策略实现类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化学生物学工具在分子，细胞和生物体水平上询问Wnt介导的信号传导，并建立在癌症背景下部署Wnt抑制剂的框架。特别是，我们专注于肺癌，因为这种疾病依赖于我们化合物组合的两个目标。这些研究应该促进从通常对快速潜水细胞有毒的一线抗癌药物过渡到那些针对个体癌症潜在遗传学的药物。

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.