(1) 基于“DNA损伤应答信号网络”，发现和验证可成药靶点
(2) 围绕肿瘤耐药和复发问题，设计和合成靶向小分子抑制剂

1、科研项目
（1）国家自然科学基金委员会，青年项目，82104206，转录因子FOXM1调控PARP抑制剂olaparib耐药性的分子机制研究，2022-01-01 至 2024-12-31，30万元，在研，主持
2、代表性科研成果
(1) 发现PARP1/2抑制剂在抑制肿瘤恶性增殖的同时，会加速肿瘤细胞周期进展和恢复精确地DNA损伤修复途径，导致适应性耐药的产生。在PARP1/2抑制剂耐受肿瘤细胞内普遍存在转录因子FOXM1的过度表达，抑制FOXM1的表达和转录活性可以显著地增加肿瘤细胞对PARP1/2抑制剂的敏感性。转录因子FOXM1抑制剂FDI-6和PARP1/2抑制剂Olaparib可以协同地抑制三阴性乳腺癌、胰腺癌等肿瘤细胞的恶性增殖。该工作的价值在于为拓展PARP1/2抑制剂适应症提供有效策略，为获得FOXM1/PARP双靶点抑制剂提供理论依据。Pharmacol Res. 2022, 175: 106040. (IF:10.334)；Cell Death. Disease 2021, 12(12):1138. (IF: 9.685)
(2) 通过融合药效团策略获得了全球首个四氢喋呤结构的BRD4/PARP双靶点抑制剂III-16。III-16是一个高选择性、高活性和低毒性的双靶点抑制剂，可以显著地抑制胰腺癌等肿瘤细胞的恶性增殖。III-16同时拓展了PARP1/2抑制剂和BRD4抑制剂单靶点抑制现有的一些局限，尤其是在拓展PARP1/2抑制剂适应症方面。III-16有望实现耐药和复发肿瘤的有效治疗。J Med Chem. 2021, 64(23): 17413-17435. (IF: 8.039)

1.Shihui Huang, Rao Cao, Qianwen Lin, Shiqi Wu, Lingli Gao, Qin Sun, Qihua Zhu, Yi Zou, Yungen Xu*, Shuping Wang*, Design, Synthesis and mechanism studies of novel dual PARP1/BRD4 inhibitors against pancreatic cancer. Eur. J Med Chem. 2022, 230:114116. (IF: 7.088)
2.Shiqi Wu, Shuhui Huang, Qianwen Lin, Yixuan Tang, Lei Huang, Yungen Xu*, Shuping Wang*, FDI-6 and Olaparib synergistically inhibit the growth of pancreatic cancer by repressing BUB1, BRCA1 and CDC25A signaling pathways. Pharmacol Res. 2022, 175: 106040. (IF:10.334)
3.Shuping Wang*, Shiqi Wu, Shihui Huang, Yixuan Tang, Liuqiong Meng, Feng Liu, Qihua Zhu, Yungen Xu*, FDI-6 inhibits the expression and function of FOXM1 to sensitize BRCA-proficient triple-negative breast cancer cells to Olaparib by regulating cell cycle progression and DNA damage repair. Cell Death. Disease 2021, 12(12):1138. (IF: 9.685)
4.Shuping Wang*, Yu Li, Shihui Huang，Shiqi Wu; Lingli Gao, Qin Sun, Qianwen Lin, Lei Huang, Liuqiong Meng, Yi Zou, Qihua Zhu*, Yungen Xu*, Discovery of Potent and Novel Dual PARP/BRD4 inhibitors for Efficient Treatment of Pancreatic Cancer. J Med Chem. 2021, 64(23): 17413-17435. (IF: 8.039)

徐云根 教授（团队PI）
朱启华 教授
邹 毅 副教授
王淑平 副教授