The binding of
peroxisome proliferator-activated receptor γ (PPARγ) to the
orphan nuclear receptor Nur77 facilitates the ubiquitination and degradation of Nur77, and leads to aberrant
fatty acid uptake for
breast cancer progression. Because of its crucial role in clinical prognosis, the interaction between Nur77 and PPARγ is an attractive target for anti-
breast-cancer therapy. However, developing an inhibitor of the Nur77-PPARγ interaction poses a technical challenge due to the absence of the crystal structure of PPARγ and its corresponding interactive model with Nur77. Here, ST-CY14, a stapled
peptide, is identified as a potent modulator of Nur77 with a KD value of 3.247 × 10-8 M by in silico analysis, rational design, and structural modification. ST-CY14 effectively increases Nur77
protein levels by blocking the Nur77-PPARγ interaction, thereby inhibiting lipid metabolism in
breast tumor cells. Notably, ST-CY14 significantly suppresses
breast cancer growth and bone
metastasis in mice. The findings demonstrate the feasibility of exploiting directly Nur77-PPARγ interaction in
breast cancer, and generate what to the best knowledge is the first direct inhibitor of the Nur77-PPARγ interaction available for impeding
fatty acid uptake and therapeutic development.