Controlling the Max Network

描述（由申请人提供）：Myc-Max转录调节因子网络在控制细胞复制、分化和凋亡中起重要作用。 Myc功能的获得是许多人类癌症的驱动力。 网络的活性取决于Max和其他网络蛋白之间二聚体的形成。 这些异二聚体的相对稳定性是控制和指导网络活性的重要因素。 我们建议确定小分子，稳定最大最大和疯狂最大二聚体。 Max-Max的稳定剂将使这种必需的二聚化配偶体不太可用于异源二聚化，并且预计会引起网络的普遍下调。 Mad-Max的稳定剂将增加Mad的抗Myc活性。 这两种类型的稳定剂将测试其在癌症中的治疗潜力。 将使用本实验室开发的用于分离Myc-Max二聚化抑制剂的基于荧光的测定法在组合化学文库中鉴定稳定剂（贝格等人，Proc Natl Acad Sci U S A 99，3830-3835（2002）。 Max-Max和Mad-Max稳定剂的生物学效应将在细胞模型中确定，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涉及蛋白质与负调节剂的暂时缔合的许多其他癌症相关控制元件。 Myc-Max网络中稳定剂的拟议工作可以为影响和指导细胞生长的新方法打开大门。

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.