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Published on: May 20, 2015
Alexidine is a TAZ-specific small-molecule inhibitor that suppresses breast cancer invasion and metastasis
Anni Ge1, Lishui Niu2, Rachel Rubino1
1Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada.
Abstract:
Breast cancer (BC) is the most diagnosed malignancy in women and often progresses to distant metastasis. Unfortunately, current treatments inadequately address the clinical needs of metastatic BC (MBC) patients. This highlights the importance of developing effective therapies for MBC patients. One of the Hippo signaling transducers, transcriptional co-activator with PDZ-binding motif (TAZ), plays a major role in BC progression. Since TAZ mostly interacts with TEAD to facilitate its function, targeting TAZ-TEAD interaction may become a treatment approach for MBC patients. To identify inhibitors of TAZ-TEAD binding, we established a sensitive TR-FRET biosensor and performed an ultra-high throughput screen. Alexidine was identified as a TAZ-TEAD binding inhibitor capable of suppressing TAZ-induced migration and invasion in BC cells as well as metastasis in bone-on-a-chip and mouse models. In conclusion, we describe a robust method for screening inhibitors of TAZ-TEAD interaction, contributing to the development of effective cancer treatments.
Insights
Researchers identified Alexidine as a drug that inhibits the TAZ-TEAD interaction, a key driver of breast cancer (BC) metastasis. This discovery offers a promising new therapeutic strategy for metastatic breast cancer (MBC) patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Breast cancer (BC) is the most common cancer in women, frequently metastasizing to distant sites.
- Current treatments for metastatic breast cancer (MBC) are insufficient, necessitating novel therapeutic strategies.
- The Hippo signaling pathway, particularly the transcriptional co-activator with PDZ-binding motif (TAZ), is implicated in BC progression.
Purpose of the Study:
- To identify inhibitors of the TAZ-TEAD interaction, a crucial complex in BC progression.
- To develop and validate a screening method for TAZ-TEAD binding inhibitors.
- To evaluate the therapeutic potential of identified inhibitors in preclinical models of BC metastasis.
Main Methods:
- Development of a sensitive time-resolved Förster resonance energy transfer (TR-FRET) biosensor for TAZ-TEAD binding.
- Ultra-high throughput screening (uHTS) of small molecules using the developed biosensor.
- In vitro assays assessing BC cell migration and invasion.
- In vivo studies using bone-on-a-chip and mouse models to evaluate anti-metastatic effects.
Main Results:
- Alexidine was identified as a potent inhibitor of the TAZ-TEAD interaction.
- Alexidine significantly suppressed TAZ-induced migration and invasion in BC cell lines.
- Alexidine demonstrated efficacy in reducing metastasis in both bone-on-a-chip and mouse models.
Conclusions:
- A robust screening method for TAZ-TEAD interaction inhibitors was established.
- Alexidine represents a promising therapeutic candidate for targeting BC metastasis.
- Targeting the TAZ-TEAD interaction offers a viable strategy for developing novel MBC treatments.
