化学
电泳剂
半胱氨酸
三阴性乳腺癌
亲核细胞
药物发现
赖氨酸
乳腺癌
组合化学
生物化学
计算生物学
癌症
酶
氨基酸
内科学
生物
催化作用
医学
作者
Shumin Lv,Fang Xu,Youlong Fan,Ke Ding,Zhengqiu Li
标识
DOI:10.1021/acs.jmedchem.2c01889
摘要
Because very few targets are currently available for drug development, triple-negative breast cancer (TNBC) has been defined as one of the most difficult diseases for chemotherapy. Herein, we describe a suite of novel electrophilic warheads, which we have used in chemical proteomics studies in a search for potential targets for TNBC. Binding site analysis revealed that these warheads can modify not only highly nucleophilic residues, including cysteine and lysine, but also weakly nucleophilic residues. Cys12 of Kirsten rat sarcoma (KRASG12C) was successfully labeled by cyclopropenone and the cyclopropeniminium ions. Moderate inhibitory activity against TNBC cells was achieved with these novel electrophile-based probes. Activity-based protein profiling reveals that these electrophiles can covalently label a series of essential protein targets, including ALDH2, LRPPRC, and FABP5 from MDA-MB-231 cells. Further functional validation experiments demonstrated that FABP5 might be a potential target for TNBC.
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