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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-11-01
|
| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383521002616 |
| _version_ | 1818425984849805312 |
|---|---|
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T14:22:38Z |
| format | Article |
| id | doaj.art-ef5672f426bd4fa496d01d9b92a63db6 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-14T14:22:38Z |
| publishDate | 2021-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-ef5672f426bd4fa496d01d9b92a63db62022-12-21T22:58:02ZengElsevierActa Pharmaceutica Sinica B2211-38352021-11-01111135673584Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagyYanan Li0Chaorong Wang1Tiantian Xu2Peichen Pan3Qing Yu4Lei Xu5Xiufang Xiong6Tingjun Hou7Sunliang Cui8Yi Sun9Cancer Institute of the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China; Cancer Center, Zhejiang University, Hangzhou 310012, ChinaCollege of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, ChinaCancer Institute of the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China; Cancer Center, Zhejiang University, Hangzhou 310012, ChinaCollege of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, ChinaCancer Institute of the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China; Cancer Center, Zhejiang University, Hangzhou 310012, ChinaInstitute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 212013, ChinaCancer Institute of the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China; Cancer Center, Zhejiang University, Hangzhou 310012, ChinaCollege of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, ChinaCollege of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Corresponding authors. Tel./fax: +86 571 86971683 (Yi Sun), +86 571 88981456 (Sunliang Cui).Cancer Institute of the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China; Cancer Center, Zhejiang University, Hangzhou 310012, China; Corresponding authors. Tel./fax: +86 571 86971683 (Yi Sun), +86 571 88981456 (Sunliang Cui).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.http://www.sciencedirect.com/science/article/pii/S2211383521002616AutophagyCullin RING ligaseER stressmTORC1NeddylationSmall molecule inhibitor |
| spellingShingle | 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 Acta Pharmaceutica Sinica B Autophagy Cullin RING ligase ER stress mTORC1 Neddylation Small molecule inhibitor |
| title | 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_short | 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 |
| topic | Autophagy Cullin RING ligase ER stress mTORC1 Neddylation Small molecule inhibitor |
| url | http://www.sciencedirect.com/science/article/pii/S2211383521002616 |
| work_keys_str_mv | AT yananli discoveryofasmallmoleculeinhibitorofcullinneddylationthattriggerserstresstoinduceautophagy AT chaorongwang discoveryofasmallmoleculeinhibitorofcullinneddylationthattriggerserstresstoinduceautophagy AT tiantianxu discoveryofasmallmoleculeinhibitorofcullinneddylationthattriggerserstresstoinduceautophagy AT peichenpan discoveryofasmallmoleculeinhibitorofcullinneddylationthattriggerserstresstoinduceautophagy AT qingyu discoveryofasmallmoleculeinhibitorofcullinneddylationthattriggerserstresstoinduceautophagy AT leixu discoveryofasmallmoleculeinhibitorofcullinneddylationthattriggerserstresstoinduceautophagy AT xiufangxiong discoveryofasmallmoleculeinhibitorofcullinneddylationthattriggerserstresstoinduceautophagy AT tingjunhou discoveryofasmallmoleculeinhibitorofcullinneddylationthattriggerserstresstoinduceautophagy AT sunliangcui discoveryofasmallmoleculeinhibitorofcullinneddylationthattriggerserstresstoinduceautophagy AT yisun discoveryofasmallmoleculeinhibitorofcullinneddylationthattriggerserstresstoinduceautophagy |