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

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 <b>A11</b> 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 <b>A11</b> toward normal L02 cells was about 10-fold less potent, indicating a much wider therapeutic window than CuB. Derivative <b>A11</b> directly binds to the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) protein with a <i>K</i>_D 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, <b>A11</b> 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.