AbstractEstrogen‐dependent cancers (breast, endometrial, and ovarian) are among the leading causes of morbidity and mortality in women worldwide. Aromatase is the main enzyme that catalyzes the biosynthesis of estrogen, which drives proliferation, and antiestrogens can inhibit the growth of these estrogen‐dependent cancers. Hu‐17, an aromatase inhibitor, is a novel small‐molecule compound that suppresses viability of and promotes apoptosis in ovarian cancer cells. Therefore, this study aimed to predict targets of Hu‐17 and assess its intracellular signaling in ovarian cancer cells. Using the Similarity Ensemble Approach software to predict the potential mechanism of Hu‐17 and combining phospho‐proteome arrays with western blot analysis, we observed that Hu‐17 could inhibit the ERK pathway, resulting in reduced estrogen synthesis in KGN cells, a cell line derived from a patient with invasive ovarian granulosa cell carcinoma. Hu‐17 reduced the expression of CYP19A1 mRNA, responsible for producing aromatase, by suppressing the phosphorylation of cAMP response element binding‐1. Hu‐17 also accelerated aromatase protein degradation but had no effect on aromatase activity. Therefore, Hu‐17 could serve as a potential treatment for estrogen‐dependent cancers albeit further investigation is warranted.