2. Academic Validation
  3. Structural Optimization of Marine Natural Product Pretrichodermamide B for the Treatment of Colon Cancer by Targeting the JAK/STAT3 Signaling Pathway

Structural Optimization of Marine Natural Product Pretrichodermamide B for the Treatment of Colon Cancer by Targeting the JAK/STAT3 Signaling Pathway

  • J Med Chem. 2024 Jun 18. doi: 10.1021/acs.jmedchem.4c00278.
Yue Zhou 1 2,  Na He 3,  Qian Liu 1 2,  Rui Li 3,  Lujia Yang 1 2,  Wei Kang 1 2,  Xinxin Zhang 3,  Xiaoyu Xu 1,  Guangshan Yao 4,  Pingyuan Wang 1 2,  Chang-Yun Wang 1 2,  Jinbo Yang 3,  Zhiqing Liu 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs and Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education), School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.
  • 2 Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao 266237, China.
  • 3 Key Laboratory of Marine Drugs of Ministry of Education & Qingdao Marine Biomedical Research Institute, Ocean University of China, Qingdao 266003, China.
  • 4 Fujian Key Laboratory on Conservation and Sustainable Utilization of Marine Biodiversity, Institute of Oceanography, Minjiang University, Fuzhou 350108, China.
PMID: 38888591 DOI: 10.1021/acs.jmedchem.4c00278
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 IC50 value of 0.12 μM against HCT116. Notably, 24 stood out with improved metabolic stability (T1/2 = 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.

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