利用 PROTAC 技术解决与抑制 BCL-X 相关的靶血小板毒性问题。
Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-X.
机构信息
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1333 Center Drive, Gainesville, FL 32610, USA.
出版信息
Chem Commun (Camb). 2019 Dec 5;55(98):14765-14768. doi: 10.1039/c9cc07217a.
Abstract
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.
摘要
BCL-XL，一种抗凋亡的 BCL-2 家族蛋白，在癌细胞存活中发挥关键作用。然而，由于血小板依赖 BCL-XL 来维持其活力，因此 BCL-XL 作为抗癌靶点的潜力受到了限制。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 细胞相对于人血小板具有更高的选择性。这项概念验证研究证明了利用 PROTAC 方法实现组织选择性的潜力。
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