基于Rucaparib的新型PARP1降解剂的设计、合成及生物活性研究

Design,synthesis and bioactivity study of the novel PARP1 degraders based on rucaparib

目的基于PROTAC原理以rucaparib为PARP1配体,设计、合成可降解PARP1蛋白的新型降解剂,以期开发新型抗肿瘤药物。方法将PARP1抑制剂rucaparib与E3连接酶配体泊马度胺通过不同的中间链进行连接,经化学合成获得目标化合物。利用Western blot研究目标化合物降解蛋白的活性与机制,并以人乳腺癌MCF-7、MDA-MB-231细胞为测试细胞株,对所合成的目标化合物进行体外抗肿瘤活性筛选。结果与结论设计并合成了7个未见文献报道的靶向PARP1的降解剂,其结构经质谱和核磁共振谱确证。其中化合物RP0、RPP3以及RPP5均具有PARP1降解活性,且RP0对PARP1的降解通过泛素蛋白酶体途径实现,值得进一步研究。

Based on the principle of PROTAC,seven novel PARP1 degraders were designed and synthesized to develop new antitumor drugs.The PARP1 inhibitor rucaparib and the E3 ligase ligand pomalidomide were linked by different intermediate chains to obtain the target compounds.The target compounds were characterized by MS and NMR.Western blot was used to examine the degradation activity and mechanism of the target compounds.MTT assay was used to evaluate the anti-proliferation effect of compounds in human breast cancer MCF-7 and MDA-MB-231 cells.The Western blot results showed that compounds RPO,RPP3 and RPP5 have PARP1 degradation activity,and RPO induces degradation of PARP1 through the ubiquitinproteasome pathway,which deserves further investigation.