Triple-negative breast cancer (TNBC) is among the most aggressive form of cancer which accounts for 15-20% of total diagnosed breast cancer cases and has high rates of metastasis and recurrence. Metastatic breast cancer remains one of the leading causes of cancer-related mortality in women. The majority of women with metastatic breast cancer relapse after curative-intent therapy for early breast cancer and a smaller proportion present with distant metastases at initial diagnosis. Our efforts of developing effective therapies for TNBC have identified CET028, a novel small molecule that effectively inhibits the growth of breast cancer cells. We found that CET028 inhibits the clonogenic potential and growth of triple-negative breast cancer cells (MDA-MB-231, MDA-MB-468, SUM159, and 4T1). CET028 treatment induces the G2/M phase cell cycle arrest in TNBC cells. Proteomics analysis suggests that it targets the protein translational process in cells. It modulates several molecules of translational complex such as RPL, RPS, and initiation factors, and thereby, causes the overall translation inhibition. Moreover, the mouse xenograft study with different TNBC cells found that CET028 inhibits growth and progression compared to the vehicle control group. Metastatic nodules in the lungs were inhibited by CET028 compared to the control group. Collectively, our <i>in vitro</i> and <i>in vivo</i> experiments, provide a strong foundation to further develop CET028 as a potential drug candidate to treat patients with TNBCs.

Small-molecule CET028 inhibits the progression of triple-negative breast cancer

ACS Spring 2022

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