MAP3K14激酶(NIK)是激活非经典NF-κB2信号通路的关键节点。NF-κB2信号通路的异常活化与部分癌症的发生发展、免疫调控和炎症诱导的肝脏组织损伤密切相关。因此，利用小分子药物抑制MAP3K14激酶活性具有治疗NF-κB2信号通路异常活化相关疾病的潜力。本项目计划开发具有优异活性和优异ADME-TOX性质的MAP3K14激酶抑制剂，研究其对于NF-κB2通路异常活化的肝脏疾病，是否具有成药性。针对MAP3K14抑制剂诱导细胞内靶点蛋白浓度升高的新发现，基于PROTAC技术设计合成MAP3K14和E3泛素酶双靶小分子，研究双靶小分子能否高效降低细胞和动物体内MAP3K14蛋白浓度，在NF-κB2通路异常活化的肿瘤细胞和动物模型内是否都具有抗癌活性。

MAP3K14 kinase (NIK) is the key regulator that activates non-canonical NF-κB2 signaling pathway. Aberrant activated NF-κB2 signaling pathway is closely related to initiation and development of certain cancer, immunological diseases and inflammation-induced liver damage. Therefore, the small-molecule MAP3K14 kinase inhibitors have therapeutic potentials for treatment of diseases associated with aberrant activated NF-κB2 signaling pathway. This project aims to design and synthesize potent MAP3K14 kinase inhibitors with optimal ADME-TOX activities. The lead compounds will be further evaluated for treatment of liver diseases that caused by aberrant activated NF-κB2 signaling pathway to prove the druggability of this hypothesis. In view of increased cellular concentration of MAP3K14 kinase in the presence of cognate kinase inhibitors, MAP3K14/E3 dual-targeted small molecules will be designed and synthesized based on PROTAC technology. Further studies will evaluate whether the dual-targeted small molecules are capable of degrading MAP3K14 kinase in intact cells and in vivo as well as have anticancer activity in vitro and in vivo.