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.
- 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].
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.