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SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy
Inhibition of the NEDD8-activating enzyme (NAE), the key E1 enzyme in the neddylation cascade, has been considered an attractive anticancer strategy with the discovery of the first-in-class NAE inhibitor, MLN4924. In this study, we identified SOMCL-19-133 as a highly potent, selective, and orally av...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352467/ https://www.ncbi.nlm.nih.gov/pubmed/35907292 http://dx.doi.org/10.1016/j.neo.2022.100823 |
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author | Zhou, Li-Na Xiong, Chaodong Cheng, Yong-Jun Song, Shan-Shan Bao, Xu-Bin Huan, Xia-Juan Wang, Tong-Yan Zhang, Ao Miao, Ze-Hong He, Jin-Xue |
author_facet | Zhou, Li-Na Xiong, Chaodong Cheng, Yong-Jun Song, Shan-Shan Bao, Xu-Bin Huan, Xia-Juan Wang, Tong-Yan Zhang, Ao Miao, Ze-Hong He, Jin-Xue |
author_sort | Zhou, Li-Na |
collection | PubMed |
description | Inhibition of the NEDD8-activating enzyme (NAE), the key E1 enzyme in the neddylation cascade, has been considered an attractive anticancer strategy with the discovery of the first-in-class NAE inhibitor, MLN4924. In this study, we identified SOMCL-19-133 as a highly potent, selective, and orally available NAE inhibitor, which is an analog to AMP. It effectively inhibited NAE with an IC(50) value of 0.36 nM and exhibited more than 2855-fold selectivity over the closely related Ubiquitin-activating enzyme (UAE). It is worth noting that treatment with SOMCL-19-133 prominently inhibited Cullin neddylation and delayed the turnover of a panel of Cullin-RING ligases (CRLs) substrates (e.g., Cdt1, p21, p27, and Wee1) at lower effective concentrations than that of MLN4924, subsequently caused DNA damage and Chk1/Chk2 activation, and thus triggered cell cycle arrest and apoptosis. Moreover, SOMCL-19-133 exhibited potent antiproliferative activity against a broad range of human tumor cell lines (mean IC(50) 201.11 nM), which was about 5.31-fold more potent than that of MLN4924. In vivo, oral delivery treatments with SOMCL-19-133, as well as the subcutaneous injection, led to significant tumor regression in mouse xenograft models. All of the treatments were well tolerated on a continuous daily dosing schedule. Compared with MLN4924, SOMCL-19-133 had a 5-fold higher peak plasma concentration, lower plasma clearance, and a 4-fold larger area under the curve (AUC(last)). In conclusion, SOMCL-19-133 is a promising preclinical candidate for treating cancers owing to its profound in vitro and in vivo efficacy and favorable pharmacokinetic properties. |
format | Online Article Text |
id | pubmed-9352467 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-93524672022-08-09 SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy Zhou, Li-Na Xiong, Chaodong Cheng, Yong-Jun Song, Shan-Shan Bao, Xu-Bin Huan, Xia-Juan Wang, Tong-Yan Zhang, Ao Miao, Ze-Hong He, Jin-Xue Neoplasia Original Research Inhibition of the NEDD8-activating enzyme (NAE), the key E1 enzyme in the neddylation cascade, has been considered an attractive anticancer strategy with the discovery of the first-in-class NAE inhibitor, MLN4924. In this study, we identified SOMCL-19-133 as a highly potent, selective, and orally available NAE inhibitor, which is an analog to AMP. It effectively inhibited NAE with an IC(50) value of 0.36 nM and exhibited more than 2855-fold selectivity over the closely related Ubiquitin-activating enzyme (UAE). It is worth noting that treatment with SOMCL-19-133 prominently inhibited Cullin neddylation and delayed the turnover of a panel of Cullin-RING ligases (CRLs) substrates (e.g., Cdt1, p21, p27, and Wee1) at lower effective concentrations than that of MLN4924, subsequently caused DNA damage and Chk1/Chk2 activation, and thus triggered cell cycle arrest and apoptosis. Moreover, SOMCL-19-133 exhibited potent antiproliferative activity against a broad range of human tumor cell lines (mean IC(50) 201.11 nM), which was about 5.31-fold more potent than that of MLN4924. In vivo, oral delivery treatments with SOMCL-19-133, as well as the subcutaneous injection, led to significant tumor regression in mouse xenograft models. All of the treatments were well tolerated on a continuous daily dosing schedule. Compared with MLN4924, SOMCL-19-133 had a 5-fold higher peak plasma concentration, lower plasma clearance, and a 4-fold larger area under the curve (AUC(last)). In conclusion, SOMCL-19-133 is a promising preclinical candidate for treating cancers owing to its profound in vitro and in vivo efficacy and favorable pharmacokinetic properties. Neoplasia Press 2022-07-27 /pmc/articles/PMC9352467/ /pubmed/35907292 http://dx.doi.org/10.1016/j.neo.2022.100823 Text en © 2022 The Authors. Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Research Zhou, Li-Na Xiong, Chaodong Cheng, Yong-Jun Song, Shan-Shan Bao, Xu-Bin Huan, Xia-Juan Wang, Tong-Yan Zhang, Ao Miao, Ze-Hong He, Jin-Xue SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy |
title | SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy |
title_full | SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy |
title_fullStr | SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy |
title_full_unstemmed | SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy |
title_short | SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy |
title_sort | somcl-19-133, a novel, selective, and orally available inhibitor of nedd8-activating enzyme (nae) for cancer therapy |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352467/ https://www.ncbi.nlm.nih.gov/pubmed/35907292 http://dx.doi.org/10.1016/j.neo.2022.100823 |
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