Abstract 5644: Identification of alexidine as a novel small molecule inhibitor of TAZ-TEAD interaction in breast cancer cell migration

Abstract Breast cancer (BC) is the most commonly diagnosed malignancy in women, with a risk of distant metastases after a primary tumor has developed. Despite concerns about the aggressive pathology of metastatic BC (MBC), current medical interventions inadequately address the clinical needs of MBC patients, resulting in worse outcomes compared to other BC cases. This highlights the critical requirement for more effective therapies for MBC patients. The Hippo pathway is often dysregulated during tumorigenesis, and one of the Hippo signaling transducers, Transcriptional co-activator with PDZ-binding motif (TAZ), is involved in multiple stages of BC development. Since TAZ mostly interacts with TEAD to facilitates its function, targeting TAZ-TEAD interaction may be a treatment approach for MBC patients. To identify small molecules that inhibit TAZ-TEAD interaction, we established a highly sensitive NanoLuc and TR-FRET applicable biosensor for quantifying protein-protein interaction of TAZ and TEAD. Using this biosensor, we performed an ultra-high throughput screen (uHTS) and identified alexidine as a novel TAZ-TEAD binding inhibitor capable of suppressing TAZ-induced migration and invasion in BC cells. In conclusion, we describe a robust method for screening inhibitors of TAZ-TEAD interaction, contributing to the development of effective cancer treatments. Citation Format: Anni Ge, Yawei Hao, Kody Klupt, Zongchao Jia, Yuhong Du, Haian Fu, Xiaolong Yang. Identification of alexidine as a novel small molecule inhibitor of TAZ-TEAD interaction in breast cancer cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5644.