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A Selective Small‐Molecule c‐Myc Degrader Potently Regresses Lethal c‐Myc Overexpressing Tumors

MYC oncogene is involved in the majority of human cancers and is often associated with poor outcomes, rendering it an extraordinarily desirable target, but therapeutic targeting of c‐Myc protein has been a challenge for >30 years. Here, WBC100, a novel oral active molecule glue that selectively d...

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Autores principales: Xu, Ying, Yu, Qingfeng, Wang, Ping, Wu, Zhaoxing, Zhang, Lei, Wu, Shuigao, Li, Mengyuan, Wu, Bowen, Li, Hongzhi, Zhuang, Haifeng, Zhang, Xuzhao, Huang, Yu, Gan, Xiaoxian, Xu, Rongzhen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8922104/
https://www.ncbi.nlm.nih.gov/pubmed/35048559
http://dx.doi.org/10.1002/advs.202104344
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author Xu, Ying
Yu, Qingfeng
Wang, Ping
Wu, Zhaoxing
Zhang, Lei
Wu, Shuigao
Li, Mengyuan
Wu, Bowen
Li, Hongzhi
Zhuang, Haifeng
Zhang, Xuzhao
Huang, Yu
Gan, Xiaoxian
Xu, Rongzhen
author_facet Xu, Ying
Yu, Qingfeng
Wang, Ping
Wu, Zhaoxing
Zhang, Lei
Wu, Shuigao
Li, Mengyuan
Wu, Bowen
Li, Hongzhi
Zhuang, Haifeng
Zhang, Xuzhao
Huang, Yu
Gan, Xiaoxian
Xu, Rongzhen
author_sort Xu, Ying
collection PubMed
description MYC oncogene is involved in the majority of human cancers and is often associated with poor outcomes, rendering it an extraordinarily desirable target, but therapeutic targeting of c‐Myc protein has been a challenge for >30 years. Here, WBC100, a novel oral active molecule glue that selectively degrades c‐Myc protein over other proteins and potently kills c‐Myc overexpressing cancer cells is reported. WBC100 targets the nuclear localization signal 1 (NLS1)–Basic–nuclear localization signal 2 (NLS2) region of c‐Myc and induces c‐Myc protein degradation through ubiquitin E3 ligase CHIP mediated 26S proteasome pathway, leading to apoptosis of cancer cells. In vivo, WBC100 potently regresses multiple lethal c‐Myc overexpressing tumors such as acute myeloid leukemia, pancreatic, and gastric cancers with good tolerability in multiple xenograft mouse models. Identification of the NLS1–Basic–NLS2 region as a druggable pocket for targeting the “undruggable” c‐Myc protein and that single‐agent WBC100 potently regresses c‐Myc overexpressing tumors through selective c‐Myc proteolysis opens new perspectives for pharmacologically intervening c‐Myc in human cancers.
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spelling pubmed-89221042022-03-21 A Selective Small‐Molecule c‐Myc Degrader Potently Regresses Lethal c‐Myc Overexpressing Tumors Xu, Ying Yu, Qingfeng Wang, Ping Wu, Zhaoxing Zhang, Lei Wu, Shuigao Li, Mengyuan Wu, Bowen Li, Hongzhi Zhuang, Haifeng Zhang, Xuzhao Huang, Yu Gan, Xiaoxian Xu, Rongzhen Adv Sci (Weinh) Research Articles MYC oncogene is involved in the majority of human cancers and is often associated with poor outcomes, rendering it an extraordinarily desirable target, but therapeutic targeting of c‐Myc protein has been a challenge for >30 years. Here, WBC100, a novel oral active molecule glue that selectively degrades c‐Myc protein over other proteins and potently kills c‐Myc overexpressing cancer cells is reported. WBC100 targets the nuclear localization signal 1 (NLS1)–Basic–nuclear localization signal 2 (NLS2) region of c‐Myc and induces c‐Myc protein degradation through ubiquitin E3 ligase CHIP mediated 26S proteasome pathway, leading to apoptosis of cancer cells. In vivo, WBC100 potently regresses multiple lethal c‐Myc overexpressing tumors such as acute myeloid leukemia, pancreatic, and gastric cancers with good tolerability in multiple xenograft mouse models. Identification of the NLS1–Basic–NLS2 region as a druggable pocket for targeting the “undruggable” c‐Myc protein and that single‐agent WBC100 potently regresses c‐Myc overexpressing tumors through selective c‐Myc proteolysis opens new perspectives for pharmacologically intervening c‐Myc in human cancers. John Wiley and Sons Inc. 2022-01-20 /pmc/articles/PMC8922104/ /pubmed/35048559 http://dx.doi.org/10.1002/advs.202104344 Text en © 2022 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Xu, Ying
Yu, Qingfeng
Wang, Ping
Wu, Zhaoxing
Zhang, Lei
Wu, Shuigao
Li, Mengyuan
Wu, Bowen
Li, Hongzhi
Zhuang, Haifeng
Zhang, Xuzhao
Huang, Yu
Gan, Xiaoxian
Xu, Rongzhen
A Selective Small‐Molecule c‐Myc Degrader Potently Regresses Lethal c‐Myc Overexpressing Tumors
title A Selective Small‐Molecule c‐Myc Degrader Potently Regresses Lethal c‐Myc Overexpressing Tumors
title_full A Selective Small‐Molecule c‐Myc Degrader Potently Regresses Lethal c‐Myc Overexpressing Tumors
title_fullStr A Selective Small‐Molecule c‐Myc Degrader Potently Regresses Lethal c‐Myc Overexpressing Tumors
title_full_unstemmed A Selective Small‐Molecule c‐Myc Degrader Potently Regresses Lethal c‐Myc Overexpressing Tumors
title_short A Selective Small‐Molecule c‐Myc Degrader Potently Regresses Lethal c‐Myc Overexpressing Tumors
title_sort selective small‐molecule c‐myc degrader potently regresses lethal c‐myc overexpressing tumors
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8922104/
https://www.ncbi.nlm.nih.gov/pubmed/35048559
http://dx.doi.org/10.1002/advs.202104344
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