Lead Compound Development of SRC-3 Inhibitors with Improved Pharmacokinetic Properties and Anticancer Efficacy

Steroid receptor coactivator 3 (SRC-3) is a critical mediator of many intracellular signaling pathways that are crucial for cancer proliferation and metastasis. In this study, we performed structure-activity relationship exploration and drug-like optimization of the hit compound , guided by / metabolism studies and cytotoxicity assays. Our efforts led to the discovery of two lead compounds, and . Both compounds exhibit potent cytotoxicity against a panel of human cancer cell lines and demonstrate acceptable pharmacokinetic properties. A biotinylated estrogen response element pull-down assay demonstrated that could disrupt the recruitment of SRC-3 and p300 in the estrogen receptor complex. Importantly, and significantly inhibited tumor growth and metastasis without appreciable acute toxicity. These results demonstrate the potential of and as drug candidates for cancer therapy, given their potent SRC-3 inhibition and promising pharmacokinetic and toxicity profiles.