新型PARP1/2抑制剂YHP-743的抗肿瘤作用

Antitumor activity of a novel PARP1/2 inhibitor YHP-743

多聚(ADP-核糖)聚合酶[poly(ADP-ribose)polymerase,PARP]-1和PARP2是参与DNA损伤修复的重要蛋白修饰酶,在多种肿瘤中处于高表达,目前已经成为肿瘤治疗的一个新靶点。本文从体外酶学、细胞及其体内动物水平评价了新型PARP1/2抑制剂YHP-743的抗肿瘤活性。结果表明,YHP-743可显著抑制PARP1和PARP2酶学活性,降低细胞内反映PARP1/2酶活性的PAR水平。在细胞水平,YHP-743可有效抑制存在同源重组基因缺陷的乳腺癌细胞的增殖,也可以与替莫唑胺、拓扑替康、顺铂、多柔比星等化疗药物联用增强其杀伤肿瘤细胞的作用。在人三阴乳腺癌细胞MX-1裸鼠异体移植瘤模型中,YHP-743与替莫唑胺联用可显著抑制肿瘤的生长。

Poly（ADP-ribose） polymerase （PARP）-I and PARP2 function as ADP-ribosylases involved in DNA repair. PARP1/2 is highly expressed in cancers and emerged as an attractive target for antitumor drug. In this study, we investigated the antitumor activity of a novel PARP1/2 inhibitor YHP-743 in vitro and in vivo. The results showed that YHP-743 had potent enzymatic inhibitory activity against PARP1 and PARP2 to down- regulate the PAR level. YHP-743 not only inhibited breast cancer cells with genes deficiency of homologous recombination repair, but also potentiated chemotherapy agent＇s cytotoxicity, such as temozolomide, topotecan, cisplatin and doxorubicin. YHP-743 elicited good antitumor activity in combination with temozolomide in vivo.