Selective degradation of BRD4 suppresses lung cancer cell proliferation using GSH-responsive PROTAC precursors
Selective degradation of BRD4 suppresses lung cancer cell proliferation using GSH-responsive PROTAC precursors
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DOI：
10.1016/j.bioorg.2023.106793
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发表时间：
2023-09-08
影响因子：
5.1
通讯作者：
Sun，Huabing
中科院分区：
文献类型：
--
作者：
Fan，Heli;Zhou，Zhili;Sun，Huabing
BRD 4作为一种转录和表观遗传调节因子，介导细胞功能，在癌症的发生发展中起着重要作用。在癌症治疗中，使用常规抑制剂靶向BRD 4需要高剂量，这通常会导致脱靶和不良反应。BRD 4靶向蛋白水解靶向嵌合体（PROTAC）可以利用内源性蛋白酶体系统催化降解BRD 4，并表现出有希望的抗肿瘤活性。然而，大多数开发的PROTAC是非癌症特异性的，并且对正常细胞具有相对毒性，限制了它们在癌症治疗中的实际应用。通过利用癌细胞中谷胱甘肽（GSH）水平高于正常细胞的优势，我们通过在VHL（von Hippel-Lindau）配体的羟基上连接GSH触发单元来募集E3连接酶，开发了几种GSH响应性PROTAC受体1a-c。在这些前体中，1可以被肺癌细胞（A549和H1299）中固有的较高浓度的GSH有效激活以释放活性PROTAC 1，降解细胞内BRD 4并导致细胞毒性，这通过机制研究证实。另一方面，在含有较低水平GSH的正常肺细胞（WI 38和HULEC-5a）中，1不能被有效地触发，因此减少了对正常细胞的不利影响。这项工作为开发刺激响应性PROTAC前体提供了另一种概念验证方法，并提供了一种新的见解，以提高选择性并最大限度地减少当前PROTAC的不良反应，从而提高其临床潜力。
BRD4, as a transcriptional and epigenetic regulator to mediate cellular functions, plays an important role in cancer development. Targeting BRD4 with conventional inhibitors in cancer therapy requires high doses, which often leads to off-target and adverse effects. BRD4-targeted proteolysis-targeting chimeras (PROTACs) can catalytically degrade BRD4 utilizing the endogenous proteasome system, and exhibit promising anti-tumor activity. However, most of the developed PROTACs are non-cancer specific and relatively toxic towards normal cells, limiting their practical applications in cancer treatment. By taking advantage of higher glutathione (GSH) levels in cancer cells than that in normal cells, we developed several GSH-responsive PROTAC precursors1a-cvia the attachment of a GSH-trigger unit on the hydroxyl group of the VHL (von Hippel-Lindau) ligand for the recruitment of E3 ligase. Among the precursors,1acan be efficiently activated by the innately higher concentrations of GSH in lung cancer cells (A549 and H1299) to release active PROTAC1, degrading intracellular BRD4 and resulting in cytotoxicity, which is confirmed by mechanistic investigation. On the other hand,1acannot be efficiently triggered in normal lung cells (WI38 and HULEC-5a) containing lower levels of GSH, therefore reducing the adverse effects on normal cells. This work provides an alternative proof of concept approach for developing stimuli-responsive PROTAC precursors, and affords a novel insight to improve the selectivity and minimize the adverse effects of current PROTACs, hence enhancing their clinical potential.