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

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.