Structural Optimization of Marine Natural Product Pretrichodermamide B for the Treatment of Colon Cancer by Targeting the JAK/STAT3 Signaling Pathway
Yue Zhou, Na He, Qian Liu, Rui Li, Lujia Yang, Wei Kang, Xinxin Zhang, Xiaoyu Xu, Guangshan Yao, Pingyuan Wang, Chang‐Yun Wang, Jinbo Yang, Zhiqing Liu
Abstract
Marine natural product (MNP) pretrichodermamide B (Pre B, 9 ) was identified as a novel STAT3 inhibitor in our previous work, while its metabolic instability hindered its further development. To address this drawback, ligand structure-based drug design was adopted leading to a series of Pre B derivatives. Among them, MNP trichodermamide B (tri B, 24 ) obtained by skeletal rearrangement exhibited more potent antiproliferative activity with an IC 50 value of 0.12 μM against HCT116. Notably, 24 stood out with improved metabolic stability ( T 1/2 = 31 min) and more favorable oral bioavailability ( F = 37.5%). Further studies indicated that 24 blocked JAK/STAT3 signaling in dose- and time-dependent manner. In vivo, 24 suppressed tumor growth (TGI = 65%) at a dose of 20 mg/kg in a HCT116-derived xenograft mouse model. Overall, 24 might be a promising lead compound for colon cancer and is worthy of further investigation.