Berberrubine is a novel and selective IMPDH2 inhibitor that impairs the growth of colorectal cancer

作者：He, Xiangli; Cui, Jiayan; Ma, Hui; Abuduaini, Naijipu; Huang, Ying; Tang, Lu; Wang, Wanyan; Zhang, Yuanyuan; Wang, Yang; Lu, Weiqiang^*; Feng, Bo^*; Huang, Jin^*

来源：Biochemical Pharmacology, 2023, 218: 115868.

DOI：10.1016/j.bcp.2023.115868

• Colorectal cancer
• IMPDH2
• Berberrubine
• Natural products

Inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting reaction in the de novo synthesis pathway of guanine nucleotides that is highly required for cancer cell outgrowth. Herein, we found that IMPDH isoform 2 (IMPDH2) is highly expressed in colorectal cancer (CRC) and is correlated with poor patient prognosis. Via structure-based virtual screening, we identified berberrubine, a critical ingredient of the medical plant Coptis chinensis, as a novel, selective, and competitive inhibitor of IMPDH2, which demonstrated over 15-fold selectivity to IMPDH2 than IMPDH1. Besides, we also confirmed the interaction between berberrubine and IMPDH2. Of note, berberrubine treatment significantly impairs the growth of human CRC cells in a dose-dependent manner, which can be rescued by supplementing with guanosine. Furthermore, oral administration of berberrubine remarkably reduced tumor volume and weight in a human cell line-derived xenograft model. Importantly, the anti-cancer activity of berberrubine was also confirmed by using the azoxymethane (AOM) / dextran sulfate sodium (DSS)-induced spontaneous CRC mouse model. Taken together, our study highlights that berberrubine acts as a novel IMPDH2 inhibitor, suppressing the growth of CRC in vitro and in vivo, providing a fresh perspective for its potential application in the treatment of CRC.

• 单位
  上海交通大学; 华东理工大学; 复旦大学; 5