(1)基于泛素-蛋白酶体通路开展小分子蛋白降解剂的发现研究
(2)靶向雌激素受体及DNA损伤修复通路的抗乳腺癌药物研发

1、科研项目
（1）国家自然科学基金青年基金项目，82103978，靶向ESR1突变体的ERα共价拮抗/降解双功能分子的发现及抗乳腺癌活性研究，2022-01-01 至 2024-12-31，30万元，在研，主持
（2）江苏省自然科学基金青年基金项目，BK20210423，靶向Y537S突变体的ERα共价降解剂的发现及抗耐药乳腺癌活性研究，2021-07 至 2024-06，20万元，在研，主持
（3）中国博士后基金面上项目，2019M662007，靶向HMGR小分子降解剂的设计、合成及调血脂活性研究，2019-11至2022-06，8万元，已结题，主持
（4）2020年度江苏省博士后日常资助，2020-09至2022-07，16万元，已结题，主持
2、代表性科研成果
(1) 针对他汀类药物易引发HMGCR蛋白代偿性升高这一科学问题，我们基于靶向嵌合体的蛋白水解（PROTAC）技术，设计、合成了一系列新型HMGCR降解剂。其中化合物21b在高脂模型鼠中表现出了较好的HMGCR降解和调血脂作用。该工作为解决他汀类药物耐药性提供了新的思路，相关成果以封面文章发表在《药学学报》英文刊（Acta Pharmaceutica Sinica B）2021年5期。

1.Luo, G.S.; Lin, X.; Vega-Medina, A.; Xiao, M.X.; Li, G.L.; Wei, H.L.; Velázquez-Martínez, C.*; Xiang, H.* Targeting of the FOXM1 oncoprotein by E3 ligase-assisted degradation. J. Med. Chem. 2021;64:17098-17114. (IF: 7.446)
2.Luo, G.S.; Li, Z.B.; Lin, X.; Li, X.Y.; Chen, Y., Xi, K.; Xiao, M.X.; Wei, H.L.; Zhu, L.Z.*; Xiang, H.* Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo. Acta Pharm. Sin. B. 2021;11:1300-1314. (IF: 11.413; Cover story)
3.Luo, G.S.1; Lin, X.1; Ren, S.L.; Wu, S.J.; Wang, X.; Ma, L.; Xiang, H.* Development of Novel Tetrahydroisoquinoline-Hydroxamate Conjugates as Potent Dual SERDs/HDAC Inhibitors for the Treatment of Breast Cancer. Eur. J. Med. Chem. 2021;226:113870. (IF: 6.514)
4.Luo, G.S.1; Lin, X.1; Li, Z.B.; Xiao, M.; Li, X.; Zhang, D.; Xiang, H*. Structure-guided modification of isoxazole-type FXR agonists: Identification of a potent and orally bioavailable FXR modulator. Eur. J. Med. Chem. 2021;209:112910. (IF: 6.514)
5.Lin, X.; Xiang, H.*; Luo, G.S.* Targeting estrogen receptor α for degradation with PROTACs: A promising approach to overcome endocrine resistance. Eur. J. Med. Chem. 2020;206:112689. (IF: 5.573)
6.Lin, X.; Lu, X.; Luo, G.S.*; Xiang, H.* Progress in PD-1/PD-L1 pathway inhibitors: From biomacromolecules to small molecules. Eur. J. Med. Chem. 2020;186:111876. (IF: 5.573)
7.Ten, Y.; Lu, X.; Xiao, M.X.; Li, Z.B.; Zou, Y.; Ren, S.; Chen, Y.; Luo, G.S.*; Xiang, H.* Discovery of potent and highly selective covalent inhibitors of Bruton tyrosine kinase bearing triazine scaffold. Eur. J. Med. Chem. 2020;199:112339. (IF: 5.573)
8.Luo, G.S.; Xiang, M.; Krische, M.J.* Successive Nucleophilic and Electrophilic Allylation for the Catalytic Enantioselective Synthesis of 2,4-Disubstituted Pyrrolidines. Org. Lett. 2019;21:2493-2497. (IF: 6.005; Cover story)
9.Luo, G.S.; Tang, Z.C.; Lao, K.; Li, X.; You, Q.D.; Xiang, H.* Structure-activity relationships of 2, 4-disubstituted pyrimidines as dual ERa/VEGFR-2 ligands with anti-breast cancer activity. Eur. J. Med. Chem. 2018;150:783-795. (IF: 4.833)
10. Luo, G.S.; Li, X.Y.; Zhan, G.Q.; Wu, C.Z.; Tang, Z.C.; Liu, L.Y.; You, Q.D.; Xiang, H.* Novel SERMs based on 3-aryl-4-aryloxy-2H-chromen-2-one skeleton - A possible way to dual ERa/VEGFR-2 ligands for treatment of breast cancer, Eur. J. Med. Chem. 2017;140:252-273. (IF: 4.833)

向华 教授团队