2. Academic Validation
  3. Discovery of unglycosylated indolocarbazoles as ROCK2 isoform-selective inhibitors for the treatment of breast cancer metastasis

Discovery of unglycosylated indolocarbazoles as ROCK2 isoform-selective inhibitors for the treatment of breast cancer metastasis

  • Eur J Med Chem. 2023 Mar 15;250:115181. doi: 10.1016/j.ejmech.2023.115181.
Jinhui Wang 1,  Tingting Gao 1,  Yijun Ma 1,  Ying Zhang 1,  Yan Yi 1,  Feihang Yan 1,  Ziyang Cheng 1,  Yalin Yu 1,  Jiaqi Li 1,  Zhe Chen 2,  Wanjing Ding 3,  Zhongjun Ma 4
Affiliations

Affiliations

  • 1 Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan, 316021, China.
  • 2 The First Affiliated Hospital of Zhejiang Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
  • 3 Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan, 316021, China; Hainan Institute of Zhejiang University, Sanya, 572025, China. Electronic address: [email protected].
  • 4 Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan, 316021, China; Hainan Institute of Zhejiang University, Sanya, 572025, China; Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China. Electronic address: [email protected].
PMID: 36764122 DOI: 10.1016/j.ejmech.2023.115181
Abstract

Breast Cancer metastasis is a major challenge in clinical therapy because of the absence of effective treatments. Rho-associated coiled-coil kinase (ROCK), which is essential for cell invasion and migration, has recently been suggested as a potential target for the treatment of Cancer metastasis. Herein, we report the structure-activity relationships (SAR) of indolocarbazoles against ROCK2 and reveal the crucial role of the C-3 hydroxyl for ROCK2 inhibition. The most potent unglycosylated aglycone THK01 was demonstrated to bind to and stabilize ROCK2 with potent anti-metastatic effects in breast Cancer in vitro and in vivo with no obvious toxicities. Further mechanistic studies revealed that the anti-metastatic effect of THK01 was closely related to the suppression of STAT3Y705 activation. Moreover, THK01 exhibited excellent selectivity over the isoform protein ROCK1 (>100-fold). Taken together, with low toxicity, the ROCK2 Inhibitor THK01 potently inhibited breast Cancer metastasis through the ROCK2-STAT3 signaling pathway, which offers a new opportunity for the treatment of metastatic breast Cancer.

Keywords

Breast cancer; Indolocarbazoles; Inhibitors; Metastasis; ROCK2.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149266
    ROCK2 Inhibitor