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Targeting GDP-Dissociation Inhibitor Beta (GDI2) with a Benzo[a]quinolizidine Library to Induce Paraptosis for Cancer Therapy

[Image: see text] 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 prote...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598831/
https://www.ncbi.nlm.nih.gov/pubmed/37885576
http://dx.doi.org/10.1021/jacsau.3c00228
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author 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
author_facet 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
author_sort Sun, Yong
collection PubMed
description [Image: see text] 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.
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spelling pubmed-105988312023-10-26 Targeting GDP-Dissociation Inhibitor Beta (GDI2) with a Benzo[a]quinolizidine Library to Induce Paraptosis for Cancer Therapy 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 JACS Au [Image: see text] 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. American Chemical Society 2023-09-26 /pmc/articles/PMC10598831/ /pubmed/37885576 http://dx.doi.org/10.1021/jacsau.3c00228 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle 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
Targeting GDP-Dissociation Inhibitor Beta (GDI2) with a Benzo[a]quinolizidine Library to Induce Paraptosis for Cancer Therapy
title Targeting GDP-Dissociation Inhibitor Beta (GDI2) with a Benzo[a]quinolizidine Library to Induce Paraptosis for Cancer Therapy
title_full Targeting GDP-Dissociation Inhibitor Beta (GDI2) with a Benzo[a]quinolizidine Library to Induce Paraptosis for Cancer Therapy
title_fullStr Targeting GDP-Dissociation Inhibitor Beta (GDI2) with a Benzo[a]quinolizidine Library to Induce Paraptosis for Cancer Therapy
title_full_unstemmed Targeting GDP-Dissociation Inhibitor Beta (GDI2) with a Benzo[a]quinolizidine Library to Induce Paraptosis for Cancer Therapy
title_short Targeting GDP-Dissociation Inhibitor Beta (GDI2) with a Benzo[a]quinolizidine Library to Induce Paraptosis for Cancer Therapy
title_sort targeting gdp-dissociation inhibitor beta (gdi2) with a benzo[a]quinolizidine library to induce paraptosis for cancer therapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598831/
https://www.ncbi.nlm.nih.gov/pubmed/37885576
http://dx.doi.org/10.1021/jacsau.3c00228
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