Wang Airong, Li Lingling, Li Mengya, Wang Shujuan, Wang Chong
Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Front Pharmacol. 2021 Apr 29;12:664176. doi: 10.3389/fphar.2021.664176. eCollection 2021.
7-Ethyl-10-hydroxycamptothecin (SN-38) is an active metabolite of CPT-11, which can inhibit DNA topoisomerase I, DNA synthesis and cause frequent DNA single-strand breaks. In our study, SN-38 was characterized as a potent and reversible BRD4 inhibitor [IC = 660.2 nM against BRD4 (BD1) and IC = 547.7 nM against BRD4 (BD2)] in biochemical assay using drug repurposing strategy. Additional cellular assay suggested that SN-38 can bind BRD4 in human leukemic cell K562 and inhibit cell growth with IC = 0.2798 μM in a BRD4 dependent manner partially. Additionally, mechanism study indicated that SN-38 can induce the accumulation of BRD4 substrate c-Myc and cleavage of caspase 3. In sum, our findings identified BRD4 as a new target of SN-38 and reveals SN-38 as a modifier of histone acetylation reader for the first time, which may provide a new insight for further optimization of dual target inhibitor.
7-乙基-10-羟基喜树碱（SN-38）是伊立替康的活性代谢产物，它能够抑制DNA拓扑异构酶I、DNA合成并导致频繁的DNA单链断裂。在我们的研究中，利用药物再利用策略，在生化分析中，SN-38被鉴定为一种强效且可逆的BRD4抑制剂[对BRD4（BD1）的IC = 660.2 nM，对BRD4（BD2）的IC = 547.7 nM]。额外的细胞分析表明，SN-38能够在人白血病细胞K562中结合BRD4，并以部分依赖BRD4的方式抑制细胞生长，IC = 0.2798 μM。此外，机制研究表明，SN-38能够诱导BRD4底物c-Myc的积累和半胱天冬酶3的裂解。总之，我们的研究结果首次确定BRD4是SN-38的新靶点，并揭示SN-38是组蛋白乙酰化阅读器的调节剂，这可能为双靶点抑制剂的进一步优化提供新的见解。
