多胺是一类具有重要生物学功能的小分子，鸟氨酸脱羧酶（ODC）是多胺合成代谢途径的限速酶。细胞中ODC活性及多胺浓度的上调与多种肿瘤发生发展高度正相关，因此ODC被认为是一个致癌蛋白酶。ODC抑制剂能够降低细胞内多胺水平，抑制肿瘤生长，但是细胞会通过反馈补偿途径，增加对胞外多胺的摄取，使ODC抑制剂在活体中疗效减弱。通过分析该领域的研究进展，结合蛋白质功能抑制剂的研究策略，本项目从蛋白相互作用与信号网络调控的角度，提出一个新的科学假设：利用小分子稳定ODC同源二聚体，达到同时抑制ODC酶活和抑制细胞外源多胺摄取能力的双重目的。前期研究中，我们综合利用多种研究手段检验了该假设的可行性，并筛选到能够稳定ODC同源二聚体和抑制ODC活性的小分子。本项目将在前期研究基础上，开展更广泛和更深入的研究，进行ODC二聚体稳定性抑制剂的大量筛选及功能和机理研究，以期为该领域的研究提供新的研究策略和工具。

Polyamines are a kind of organic small molecules important to many normal cellular functions. In human cells, ornithine decarboxylase (ODC) is the rate-limiting enzyme of the polyamine biosynthetic pathway. Studies have shown that the upregulation of ODC enzymatic activity and polyamines’ concentrations in human cells are positively correlated with the origination and development of many kinds of tumors. Therefore, ODC is likely an oncogenetic enzyme. In the past years, ODC inhibitors have been proved to be able to decrease the concentrations of polyamines in cells, and inhibit the growth of cancer cells. However, ODC inhibitors showed little or no efficacy in vivo, due to the increased uptake of exogenous polyamines by cancer cells, which is induced by the compensatory feedback mechanism of the polyamine regulation system. After thoroughly analyzing the research progress in this field, stimulated by the strategies of designing protein-protein interaction inhibitors, and from the viewpoint of systems biology, we are presenting a new scientific hypothesis in this research project: an ODC homodimer stabilizer might be able to inhibit the enzymatic activity of ODC, and at the same time, inhibit the compensatory feedback pathway of the polyamine regulation network. In our preliminary study, by combining a series of research tools, we validated the rationale of this hypothesis and discovered small molecules that can stabilize ODC homodimer and inhibit ODC enzymatic activity. Therefore, in this project, based on our preliminary study, we will do more work to screen and optimize ODC-dimer-stabilizing inhibitors, and study the molecular and cellular mechanism of this kind of ODC inhibitors. We hope the work in this project could validate our scientific hypothesis, and then provide a new research strategy and new research tools to the research field of polyamines.