Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-XL.
Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-XL.
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DOI：
10.1039/c9cc07217a
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发表时间：
2019-11
影响因子：
4.9
通讯作者：
Xuan Zhang;Dinesh Thummuri;Yonghan He;Xingui Liu;Peiyi Zhang;Daohong Zhou;Guangrong Zheng
中科院分区：
文献类型：
--
作者：
Xuan Zhang;Dinesh Thummuri;Yonghan He;Xingui Liu;Peiyi Zhang;Daohong Zhou;Guangrong Zheng
BCL-XL是一种抗凋亡的BCL-2家族蛋白，对肿瘤细胞的存活起着关键作用。然而，bclxl作为抗癌靶点的潜力一直受到靶点上的血小板毒性的阻碍，因为血小板依赖bclxl维持其活性。在这里，我们报告了一种PROTAC BCL-XL降解剂XZ424的开发，与传统的BCL-XL抑制剂相比，它对依赖BCL-XL的MOLT-4细胞比对人血小板的选择性更高。这项概念验证研究展示了利用PROTAC方法实现组织选择性的潜力。
BCL-XL, an anti-apoptotic BCL-2 family protein, plays a key role in cancer cell survival. However, the potential of BCL-XL as an anti-cancer target has been hampered by the on-target platelet toxicity because platelets depend on BCL-XL to maintain their viability. Here we report the development of a PROTAC BCL-XL degrader, XZ424, which has increased selectivity for BCL-XL-dependent MOLT-4 cells over human platelets compared with conventional BCL-XL inhibitors. This proof-of-concept study demonstrates the potential of utilizing a PROTAC approach to achieve tissue selectivity.