N-Myc异常激活的神经母细胞瘤药物新靶点发现和创新药物研究

N-Myc是神经母细胞瘤发生发展的关键因子，其基因扩增与患者预后不良密切相关，是临床治疗亟需解决的关键问题。我们前期利用小分子探针研究发现，蛋白修饰酶DHHC22和KLHL37对N-Myc具有重要调控作用，其中DHHC22可通过对N-Myc进行棕榈酰化修饰促进肿瘤化疗抵抗，而KLHL37则可通过抑制N-Myc的泛素化降解促进肿瘤转移，提示蛋白修饰的动态失衡可能是N-Myc异常激活导致神经母细胞瘤不良预后的关键环节。本项目将进一步研究棕榈酰化、泛素化等蛋白修饰失衡在N-Myc驱动神经母细胞瘤恶性演进中的作用，阐明修饰酶DHHC22和KLHL37的激活对N-Myc信号的影响及其分子过程；并将以上述修饰酶为靶点，构建药物筛选模型，发现先导小分子。本项目有望揭示不同蛋白修饰酶通过调控N-Myc从而促进神经母细胞瘤恶性演进的新机制，发现治疗神经母细胞瘤的新靶标及先导小分子，为其临床治疗提供新策略。

N-Myc abnormal activation is the critical contributor to the initiation and development of neuroblastoma, and it is closely related to the poor prognosis of neuroblastoma patients. Thus, it is urgent to inhibit the activation of N-Myc for the clinical treatment of neuroblastoma. However, N-Myc is commonly recognized as an undruggable target, so it is important to find key targetable molecules that can regulate N-Myc signaling. In our previous studies, we have found that the protein-modifying enzymes DHHC22 and KLHL37 can specifically regulate N-Myc activity. DHHC22 can promote the palmitoylation of N-Myc to induce the chemotherapy resistance of neuroblastoma, while KLHL37 can inhibit the ubiquitination degradation of N-Myc to promote the metastasis of neuroblastoma. These results suggest that the dynamic imbalance of N-Myc protein modification may account for its abnormal activation, finally leading to the poor prognosis of neuroblastoma patients. Therefore, our research will further clarify the influence of palmitoylation, ubiquitination and other protein modification dynamic imbalances in malignant progression of neuroblastoma driven by aberrant N-Myc activation. Then we will study the roles of protein-modifying enzymes like DHHC22 and KLHL37 in N-Myc regulation. Moreover, we will screen for the lead compounds targeting DHHC22 and KLHL37 for the clinical treatment of N-Myc-driven neuroblastoma. Our study is expected to reveal the molecular processes that different protein-modifying enzymes promote the malignant progression of neuroblastoma through regulating N-Myc activity, and discover potential drug targets as well as lead compounds to provide novel therapeutic strategies for neuroblastoma eradication.