Open AccessA Selective Small‐Molecule c‐Myc Degrader Potently Regresses Lethal c‐Myc Overexpressing Tumors
Author(s) -
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
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202104344
Subject(s) - cancer research , synthetic lethality , ubiquitin ligase , oncogene , ubiquitin , chemistry , biology , apoptosis , gene , cell cycle , dna repair , biochemistry
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.