A First-in-Class Inhibitor of ER Coregulator PELP1 Targets ER+ Breast Cancer.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Estrogen receptor-positive (ER+) breast cancer often develops therapy resistance.
• Overexpression of PELP1 contributes to breast cancer progression and resistance.
• There is a need for novel small molecule inhibitors targeting PELP1.

Purpose of the Study:

• To identify and develop novel inhibitors of PELP1.
• To evaluate the efficacy of a new PELP1 inhibitor, SMIP34, in preclinical models of ER+ breast cancer.

Main Methods:

• Yeast-two-hybrid screening to identify peptide inhibitors of PELP1.
• Biochemical and computational modeling to characterize inhibitor-target interactions.
• In vitro studies using breast cancer cell lines (WT and MT).
• In vivo studies using xenograft models (cell line- and patient-derived).

Main Results:

• Identified peptide inhibitors of PELP1 (PIP), including PIP1.
• Developed SMIP34, a small molecule inhibitor that directly binds PELP1.
• SMIP34 inhibited proliferation of ER+ breast cancer cells, including therapy-resistant types.
• SMIP34 induced PELP1 degradation via the proteasome pathway.
• SMIP34 suppressed tumor growth in both WT and MT ER+ breast cancer xenograft models.

Conclusions:

• SMIP34 is a first-in-class inhibitor of oncogenic PELP1 signaling.
• SMIP34 demonstrates therapeutic potential for advanced and therapy-resistant ER+ breast cancer.