Controlling the Max Network

描述(由申请人提供)：Myc-Max转录调控网络在控制细胞复制、分化和凋亡方面发挥着重要作用。Myc功能的获得是许多人类癌症的驱动力。该网络的活性取决于MAX和其他网络蛋白之间二聚体的形成。这些杂二聚体的相对稳定性是控制和指导网络活性的重要因素。 我们建议识别稳定Max-Max和Mad-Max二聚体的小分子。MAX-MAX的稳定剂将使这一重要的二聚化伙伴较少可用于异二聚化，并预计将导致网络的普遍下调。Mad-Max的稳定剂可提高Mad的抗Myc活性。这两种稳定剂都将接受癌症治疗潜力的测试。 将使用本实验室为分离Myc-Max二聚化抑制剂而开发的基于荧光的分析方法，在组合化学库中确定稳定剂(Berg等人。《国家学报》，S，A 99，第3830-3835页(2002年)。Max-Max和Mad-Max稳定剂的生物学效应将在细胞模型中确定，以测试Myc的功能。用蛋白质二聚体的小分子稳定剂调节细胞功能的原理也适用于细胞中许多其他与癌症相关的控制元件，这些元件涉及蛋白质与负调节因子的临时结合。关于Myc-Max网络中稳定剂的拟议工作可能会打开一种影响和指导细胞生长的新途径。

DESCRIPTION (provided by applicant): The Myc-Max network of transcriptional regulators plays an important role in the control of cell replication, differentiation, and apoptosis. Gain of Myc function is a driving force in numerous human cancers. The activity of the network depends on the formation of dimers between Max and other network proteins. The relative stabilities of these heterodimers are important factors that control and direct network activity. We propose to identify small molecules that stabilize Max-Max and Mad-Max dimers. Stabilizers of Max-Max would make this essential dimerization partner less available for heterodimerization and are expected to cause a general downregulation of the network. Stabilizers of Mad-Max would increase the anti-Myc activity of Mad. Both types of stabilizers will be tested for their therapeutic potential in cancer. Stabilizers will be identified in combinatorial chemical libraries using fluorescence-based assays developed in this laboratory for isolating inhibitors of Myc-Max dimerization (Berg et al. Proc Natl Acad Sci U S A 99, 3830-3835 (2002). The biological effects of Max-Max and Mad-Max stabilizers will be determined in cellular models, testing the functions of Myc. The principle of regulating cellular functions with small molecule stabilizers of protein dimers is also applicable to numerous other cancer-related control elements in the cell that involve the temporary association of a protein with a negative regulator. The proposed work on stabilizers in the Myc-Max network could open the door to a new way of influencing and directing cell growth.