2. Academic Validation
  3. Discovery of Triazolyl Derivatives of Cucurbitacin B Targeting IGF2BP1 against Non-Small Cell Lung Cancer

Discovery of Triazolyl Derivatives of Cucurbitacin B Targeting IGF2BP1 against Non-Small Cell Lung Cancer

  • J Med Chem. 2023 Sep 28;66(18):12931-12949. doi: 10.1021/acs.jmedchem.3c00872.
Fan-Fan Shang 1 2,  Qing Lu 2,  Tailiang Lin 2,  Miaoxia Pu 1 3,  Ruoxuan Xiao 2,  Wanmei Liu 2,  Hao Deng 1,  Hongyan Guo 1,  Zhe-Shan Quan 1,  Chunyong Ding 2,  Qing-Kun Shen 1
Affiliations

Affiliations

  • 1 Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, China.
  • 2 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 3 Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Integration Science, Yanbian University, Yanji 133002, China.
PMID: 37681508 DOI: 10.1021/acs.jmedchem.3c00872
Abstract

Cucurbitacin B (CuB) is a potent but toxic Anticancer natural product. Herein, we designed and synthesized 2-OH- and 16-OH-modified CuB derivatives to improve their antitumor efficacy and reduce toxicity. Among them, derivative A11 had the most potent antiproliferative activity against A549 lung Cancer cells (IC50 = 0.009 μM) and was approximately 10-fold more potent than CuB, while the cytotoxicity of A11 toward normal L02 cells was about 10-fold less potent, indicating a much wider therapeutic window than CuB. Derivative A11 directly binds to the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) protein with a KD value of 2.88 nM, which is about 23-fold more potent than CuB, leading to the decreased expression of downstream apoptosis- and cell cycle-related proteins. More importantly, A11 exhibited much more potent Anticancer efficacy in an A549 xenograft mouse model with a TGI rate of 80% and a superior in vivo safety profile than that of CuB.

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