Targeting GDP-Dissociation Inhibitor Beta (GDI2) with a Benzo[a]quinolizidine Library to Induce Paraptosis for Cancer Therapy.
Targeting GDP-Dissociation Inhibitor Beta (GDI2) with a Benzo[a]quinolizidine Library to Induce Paraptosis for Cancer Therapy.
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DOI：
10.1021/jacsau.3c00228
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发表时间：
2023-10-23
期刊：
影响因子：
8
通讯作者：
Lou, Hongxiang
中科院分区：
文献类型：
--
作者：
Sun, Yong;Zheng, Hongbo;Qian, Lilin;Liu, Yue;Zhu, Deyu;Xu, Zejun;Chang, Wenqiang;Xu, Jianwei;Wang, Lei;Sun, Bin;Gu, Lichuan;Yuan, Huiqing;Lou, Hongxiang
诱导细胞凋亡是一种非凋亡的细胞死亡形式，在癌症治疗中具有巨大的治疗潜力，特别是对耐药肿瘤。然而，触发细胞凋亡的具体分子靶点尚未被破译。在此，通过基于活性的蛋白分析，我们确定了gdp解离抑制剂β (GDI2)是诱导细胞凋亡的可操纵靶点，并发现苯并[a]喹诺齐啶BQZ-485通过与Tyr245的相互作用作为GDI2的有效抑制剂。综合靶标验证表明，BQZ-485破坏了内在的GDI2-Rab1A相互作用，从而破坏了从内质网（ER）到高尔基体的囊泡运输，并启动了随后的细胞凋亡事件，包括内质网扩张和融合、内质网应激、未折叠蛋白反应和细胞质空泡化。基于BQZ-485的结构，我们通过点击化学建立了一个小的苯并[a]喹诺齐啶文库，并利用基于nanoluc的筛选平台发现了更有效的GDI2抑制剂。利用BQZ-485与GDI2的接合，我们开发了一种选择性GDI2降解器。本研究中优化的抑制剂(+)-37和降解剂21在两种过表达gdi2的胰腺异种移植模型（包括AsPc-1实体瘤模型和移植的人PDAC肿瘤模型）中表现出出色的体内抗肿瘤活性。总之，我们的研究结果为靶向GDI2治疗胰腺癌细胞凋亡提供了一个有希望的策略，这些先导化合物可以进一步优化为有效的化疗药物。
Inducing paraptosis, a nonapoptotic form of cell death, has great therapeutic potential in cancer therapy, especially for drug-resistant tumors. However, the specific molecular target(s) that trigger paraptosis have not yet been deciphered yet. Herein, by using activity-based protein profiling, we identified the GDP-dissociation inhibitor beta (GDI2) as a manipulable target for inducing paraptosis and uncovered benzo[a]quinolizidine BQZ-485 as a potent inhibitor of GDI2 through the interaction with Tyr245. Comprehensive target validation revealed that BQZ-485 disrupts the intrinsic GDI2-Rab1A interaction, thereby abolishing vesicular transport from the endoplasmic reticulum (ER) to the Golgi apparatus and initiating subsequent paraptosis events including ER dilation and fusion, ER stress, the unfolded protein response, and cytoplasmic vacuolization. Based on the structure of BQZ-485, we created a small benzo[a]quinolizidine library by click chemistry and discovered more potent GDI2 inhibitors using a NanoLuc-based screening platform. Leveraging the engagement of BQZ-485 with GDI2, we developed a selective GDI2 degrader. The optimized inhibitor (+)-37 and degrader 21 described in this study exhibited excellent in vivo antitumor activity in two GDI2-overexpressing pancreatic xenograft models, including an AsPc-1 solid tumor model and a transplanted human PDAC tumor model. Altogether, our findings provide a promising strategy for targeting GDI2 for paraptosis in the treatment of pancreatic cancers, and these lead compounds could be further optimized to be effective chemotherapeutics.