癌症研究
平方毫米
威尼斯人
髓系白血病
白血病
阿糖胞苷
彪马
医学
细胞凋亡
生物
免疫学
慢性淋巴细胞白血病
生物化学
作者
Bridget Marcellino,Xiaobao Yang,H. Ümit Kanıskan,Claudia Brady,He Chen,Karie Chen,Xing Qiu,Cara Clementelli,Lauren Herschbein,Zhijun Li,Sebastian Elghaity-Beckley,Joann Arandela,Brianna Kelly,Ronald Hoffman,Jing Liu,Yue Xiong,Jian Jin,Alan H. Shih
出处
期刊:Leukemia
[Springer Nature]
日期:2022-10-29
卷期号:37 (2): 370-378
被引量:10
标识
DOI:10.1038/s41375-022-01735-6
摘要
In acute myeloid leukemia (AML), p53 tumor suppressor activity can be reduced due to enhanced expression of MDM2 which promotes the degradation of p53. In TP53 wild-type malignancies, therapy with small molecule antagonists of MDM2 results in antileukemic activity. Current treatment strategies, however, have been limited by poor tolerability and incomplete clinical activity. We have developed a proteolysis-targeting chimera (PROTAC) MS3227 that targets MDM2 by recruiting the E3 ligase Von Hippel-Lindau, resulting in proteasome-dependent degradation of MDM2. In WT TP53 leukemia cell lines, MS3227 led to activation of p53 targets p21, PUMA, and MDM2 and resulted in cell-cycle arrest, apoptosis, and decreased viability. The catalytic PROTAC MS3227 led to more potent activation when compared to a stoichiometric inhibitor, in part by dampening the negative feedback mechanism in the p53 - MDM2 circuit. The effectiveness of MS3227 was also observed in primary patient specimens with selectivity towards leukemic blasts. The addition of MS3227 enhanced the activity of other anti-leukemic agents including azacytidine, cytarabine, and venetoclax. In particular, MS3227 treatment was shown to downregulate MCL-1, a known mediator of resistance to venetoclax. A PROTAC-based approach may provide a means of improving MDM2 inhibition to gain greater therapeutic potential in AML.
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