本项目提出NQO1靶向ROS诱导剂的抗肿瘤药物研发应注重NQO1/CPR选择性，以避免CPR介导的肝毒性。目前报道的NQO1醌底物普遍缺乏NQO1/CPR选择性。本课题组前期发现了具有一定NQO1/CPR选择性的醌类底物DDO-7134及结构新颖的非醌底物000A-0055，对正常肝脏细胞毒性较小。本项目将以这两个化合物为先导物，从靶标-底物结合的形状匹配、电性匹配及底物分子的氧化还原电位角度，深入研究“构-效”及“构-选择性”关系，优化NQO1靶向ROS诱导活性及NQO1/CPR选择性，综合考虑体内外抗肿瘤活性及成药性质（水溶性、logD、透膜性等理化性质，ADME药代动力学性质及肝毒性等）进行结构优化，以期发现高效低毒、结构新颖的高选择性NQO1靶向ROS诱导剂作为抗肿瘤及抗耐药肿瘤的候选药物，结合本课题组前期开发的NQO1小分子荧光探针，探索其在NQO1高表达肿瘤个体化治疗中的应用。

In this project we propose that it is of important to pay great attention to the selectivity between NQO1 and CPR during the research and development of NQO1-targeted ROS-inducers as antitumor agents and thus to avoid the potential hepatotoxicity that caused by CPR. However, the currently reported NQO1 substrates can also be catalyzed by CPR and showed poor NQO1/CPR selectivity. Our research group has recently discovered the quinonoid substrate DDO-7134 and novel non-quinonoid substrate 000A-0055 that showed appropriate NQO1/CPR selectivity and low toxicity toward normal liver cells. Taking these two compounds as the lead compounds, we plan to further carry on the structure-activity relationship (SAR) and structure-selectivity relationship (SSR) studies by analyzing the aspects of molecular shape and electric property for target-substrate interaction and redox potential for substrates, and to optimize both of the NQO1-targeted ROS inducing activity and NQO1/CPR selectivity. With fully consideration of the in vitro and in vivo antitumor activity, NQO1/CPR selectivity, and druggable properties such as aqueous solubility, log D, permeability, ADME pharmacokinetic properties and hepatotoxicity during the structural optimization, we prospect to discover highly selective NQO1-targeted ROS-inducers with novel structures, high potency and low toxicity as promising antitumor candidates for the treatment of NQO1-overexpressed cancers and drug-resistant cancers as well. Utilizing the small molecular fluorescent probe for NQO1 recently developed by our group, We plan to explore the application of the antitumor candidates in individualized treatment for NQO1-overexpressed cancers.