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

J Med Chem

Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, China.

Published: September 2023

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 had the most potent antiproliferative activity against A549 lung cancer cells (IC = 0.009 μM) and was approximately 10-fold more potent than CuB, while the cytotoxicity of toward normal L02 cells was about 10-fold less potent, indicating a much wider therapeutic window than CuB. Derivative directly binds to the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) protein with a 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, 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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http://dx.doi.org/10.1021/acs.jmedchem.3c00872DOI Listing

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