Design,synthesis and bioactivity study of the novel PARP1 degraders based on rucaparib
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 RP0,RPP3 and RPP5 have PARP1 degradation activity,and RP0 induces degradation of PARP1 through the ubiquitin-proteasome pathway,which deserves further investigation.
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