Lyu Peng, Jiang Kaili, Zhou Yuee, Hu Jun, Chang Yu, Zhang Zhang, Huang Minhao, Zhang Zhi-Min, Ding Ke, Hao Piliang, Lin Ligen, Li Zhengqiu
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau 999078, China.
School of Pharmacy, Jinan University, Guangzhou 510632, China.
ACS Med Chem Lett. 2022 Jan 19;13(2):292-297. doi: 10.1021/acsmedchemlett.1c00651. eCollection 2022 Feb 10.
Target identification is an essential step in drug discovery. It facilitates an understanding of drug action and potential toxicities and offers opportunities to repurpose drug candidates. HP-1, a potent EGFR (epidermal growth factor receptor) mutant inhibitor, was developed by the group in an effort to treat acquired resistance in nonsmall cell lung cancer (NSCLC), but its cellular off-targets were not identified. An activity-based probe, HJ-1, was created followed by chemical proteomics and bioimaging studies. A total of 13 protein hits, including EGFR and NT5DC1, were identified by pull-down/LC-MS. Subsequent validation experiments indicated the involvement of a major off-target, NT5DC1, in the biological function of HP-1.
靶点识别是药物研发中的关键步骤。它有助于理解药物作用及潜在毒性，并为重新利用候选药物提供机会。HP-1是一种强效的表皮生长因子受体（EGFR）突变抑制剂，该团队开发它是为了治疗非小细胞肺癌（NSCLC）中的获得性耐药，但尚未确定其细胞脱靶效应。基于活性的探针HJ-1随后通过化学蛋白质组学和生物成像研究创建。通过下拉/液相色谱-质谱联用共鉴定出13种蛋白质，包括EGFR和NT5DC1。随后的验证实验表明，主要脱靶蛋白NT5DC1参与了HP-1的生物学功能。
