Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy

Protein neddylation is catalyzed by a three-enzyme cascade, namely an E1 NEDD8-activating enzyme (NAE), one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases. The physiological substrates of neddylation are the family members of cullin, the scaffold component of cullin RING lig...

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Autores principales:	Yanan Li, Chaorong Wang, Tiantian Xu, Peichen Pan, Qing Yu, Lei Xu, Xiufang Xiong, Tingjun Hou, Sunliang Cui, Yi Sun
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Autophagy Cullin RING ligase ER stress mTORC1 Neddylation Small molecule inhibitor Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/ef5672f426bd4fa496d01d9b92a63db6
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spelling	oai:doaj.org-article:ef5672f426bd4fa496d01d9b92a63db62021-12-02T05:01:25ZDiscovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy2211-383510.1016/j.apsb.2021.07.012https://doaj.org/article/ef5672f426bd4fa496d01d9b92a63db62021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2211383521002616https://doaj.org/toc/2211-3835Protein neddylation is catalyzed by a three-enzyme cascade, namely an E1 NEDD8-activating enzyme (NAE), one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases. The physiological substrates of neddylation are the family members of cullin, the scaffold component of cullin RING ligases (CRLs). Currently, a potent E1 inhibitor, MLN4924, also known as pevonedistat, is in several clinical trials for anti-cancer therapy. Here we report the discovery, through virtual screening and structural modifications, of a small molecule compound HA-1141 that directly binds to NAE in both in vitro and in vivo assays and effectively inhibits neddylation of cullins 1–5. Surprisingly, unlike MLN4924, HA-1141 also triggers non-canonical endoplasmic reticulum (ER) stress and PKR-mediated terminal integrated stress response (ISR) to activate ATF4 at an early stage, and to inhibit protein synthesis and mTORC1 activity at a later stage, eventually leading to autophagy induction. Biologically, HA-1141 suppresses growth and survival of cultured lung cancer cells and tumor growth in in vivo xenograft lung cancer models at a well-tolerated dose. Taken together, our study has identified a small molecule compound with the dual activities of blocking neddylation and triggering ER stress, leading to growth suppression of cancer cells.Yanan LiChaorong WangTiantian XuPeichen PanQing YuLei XuXiufang XiongTingjun HouSunliang CuiYi SunElsevierarticleAutophagyCullin RING ligaseER stressmTORC1NeddylationSmall molecule inhibitorTherapeutics. PharmacologyRM1-950ENActa Pharmaceutica Sinica B, Vol 11, Iss 11, Pp 3567-3584 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Autophagy Cullin RING ligase ER stress mTORC1 Neddylation Small molecule inhibitor Therapeutics. Pharmacology RM1-950
spellingShingle	Autophagy Cullin RING ligase ER stress mTORC1 Neddylation Small molecule inhibitor Therapeutics. Pharmacology RM1-950 Yanan Li Chaorong Wang Tiantian Xu Peichen Pan Qing Yu Lei Xu Xiufang Xiong Tingjun Hou Sunliang Cui Yi Sun Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy
description	Protein neddylation is catalyzed by a three-enzyme cascade, namely an E1 NEDD8-activating enzyme (NAE), one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases. The physiological substrates of neddylation are the family members of cullin, the scaffold component of cullin RING ligases (CRLs). Currently, a potent E1 inhibitor, MLN4924, also known as pevonedistat, is in several clinical trials for anti-cancer therapy. Here we report the discovery, through virtual screening and structural modifications, of a small molecule compound HA-1141 that directly binds to NAE in both in vitro and in vivo assays and effectively inhibits neddylation of cullins 1–5. Surprisingly, unlike MLN4924, HA-1141 also triggers non-canonical endoplasmic reticulum (ER) stress and PKR-mediated terminal integrated stress response (ISR) to activate ATF4 at an early stage, and to inhibit protein synthesis and mTORC1 activity at a later stage, eventually leading to autophagy induction. Biologically, HA-1141 suppresses growth and survival of cultured lung cancer cells and tumor growth in in vivo xenograft lung cancer models at a well-tolerated dose. Taken together, our study has identified a small molecule compound with the dual activities of blocking neddylation and triggering ER stress, leading to growth suppression of cancer cells.
format	article
author	Yanan Li Chaorong Wang Tiantian Xu Peichen Pan Qing Yu Lei Xu Xiufang Xiong Tingjun Hou Sunliang Cui Yi Sun
author_facet	Yanan Li Chaorong Wang Tiantian Xu Peichen Pan Qing Yu Lei Xu Xiufang Xiong Tingjun Hou Sunliang Cui Yi Sun
author_sort	Yanan Li
title	Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy
title_short	Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy
title_full	Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy
title_fullStr	Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy
title_full_unstemmed	Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy
title_sort	discovery of a small molecule inhibitor of cullin neddylation that triggers er stress to induce autophagy
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/ef5672f426bd4fa496d01d9b92a63db6
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Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy

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