作者
Sajid Khan, Xuan Zhang, Dongwen Lv, Qi Zhang, Yonghan He, Peiyi Zhang, Xingui Liu, Dinesh Thummuri, Yaxia Yuan, Janet S Wiegand, Jing Pei, Weizhou Zhang, Abhisheak Sharma, Christopher R McCurdy, Vinitha M Kuruvilla, Natalia Baran, Adolfo A Ferrando, Yong-mi Kim, Anna Rogojina, Peter J Houghton, Guangcun Huang, Robert Hromas, Marina Konopleva, Guangrong Zheng, Daohong Zhou
发表日期
2019/12
期刊
Nature medicine
卷号
25
期号
12
页码范围
1938-1947
出版商
Nature Publishing Group US
简介
B-cell lymphoma extra large (BCL-XL) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-XL inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-XL proteolysis-targeting chimera (PROTAC), that targets BCL-XL to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-XL-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug …
学术搜索中的文章
S Khan, X Zhang, D Lv, Q Zhang, Y He, P Zhang, X Liu… - Nature medicine, 2019