CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences , Chinese Academy of Sciences , Shanghai 200032 , China.
School of Chemical Biology and Biotechnology , Peking University Shenzhen Graduate School , Shenzhen 518055 , China.
Mol Pharm. 2018 Aug 6;15(8):3252-3259. doi: 10.1021/acs.molpharmaceut.8b00325. Epub 2018 Jul 24.
LRRK2-IN-1, one of the first selective inhibitors of leucine-rich repeat kinase 2 (LRRK2), was serendipitously found to exhibit potent antiproliferative activity in several types of human cancer cells. In this study, we employed a chemoproteomic strategy utilizing a photoaffinity probe to identify the cellular target(s) of LRRK2-IN-1 underlying its anticancer activity. LRRK2-IN-1 was found to induce cell cycle arrest as well as cancer cell death by specifically binding to human proliferating cell nuclear antigen (PCNA) in cancer cells. Our current findings suggest the potential of LRRK2-IN-1 as a novel pharmacological molecule for scrutinizing cell physiology and furnish a logical foundation for the future development of therapeutic reagents for cancer.
LRRK2-IN-1 是一种新型选择性的富亮氨酸重复激酶 2（LRRK2）抑制剂，在几种人类癌细胞中被意外发现具有很强的抗增殖活性。在这项研究中，我们采用化学蛋白质组学策略，利用光亲和探针来鉴定 LRRK2-IN-1 的抗癌活性的细胞靶标。研究发现，LRRK2-IN-1 通过特异性结合癌细胞中的增殖细胞核抗原（PCNA）诱导细胞周期停滞和癌细胞死亡。我们的研究结果表明，LRRK2-IN-1 作为一种研究细胞生理学的新型药理学分子具有潜力，并为未来癌症治疗试剂的开发提供了合理的基础。
