The transcriptional coactivator with a PDZ-binding motif (TAZ, also called WWTR1) acts as an N-terminal TEAD-binding domain, one or two WW domains, and a transcriptional activation domain. The Hippo pathway acts as a tumor suppressor signaling pathway.

In human cancers, the Hippo pathway is frequently compromised, resulting in TAZ hyperactivity. TAZ gene amplification is also detected in cancers. TAZ hyperactivity causes EMT and provides cancer cells with stemness. Hence, TAZ represents considered a potential cancer therapeutic target. The transforming ability of TAZ attributes mostly to the interaction with TEAD and Wbp2. Besides TEAD and Wbp2, TAZ interacts with numerous transcriptional factors. TAZ interacts with thyroid transcription factor 1, Pax8, and T-box transcription factor 5. It also interacts with p300. In human embryonic stem cells, TAZ interacts with SMAD2, -3, and -4 and is essential for the maintenance of self-renewal.

Although the role of TAZ in the maintenance of muscle satellite cells remains to be clarified, considering the potential role of TAZ in myogenesis, we expected that TAZ activators are beneficial for the therapy of sarcopenia. Hence, scientists established a cell-based assay for TAZ activators, screened 18,458 chemical compounds, and obtained 50 TAZ activator candidates. Today, we would like to introduce a TAZ activator, IBS008738.

IBS008738 is a potent TAZ activator.

The compound stabilizes TAZ, increases the unphosphorylated TAZ level, enhances the association of MyoD with the myogenin promoter, upregulates MyoD-dependent gene transcription, and competes with myostatin in C2C12 cells. IBS008738 enhances myogenesis in C2C12 cells and facilitates muscle repair in a muscle injury model.

IBS008738 (0, 24, 48, 72 h) enhances TAZ expression, with a peak at 24 h. And IBS008738 (10 μM; 0, 24, 72 h) enhances mRNAs of myogenic markers but not of myofusion markers. Moreover, IBS008738 (10 μM; 24h) enhances mRNAs of IL-10 in C2C12 cells. In addition, IBS008738 (3 nmol) facilitates muscle repair in Cardiotoxin-injected muscles.

IBS008738 (100-μL volume of 30 μM; intramuscular injection; immediately and on day 2 after TBI) diminishes the expression of TNF α and IL-6 but increases that of IL-10 mRNAs in muscles of traumatic brain injury (TBI).

Reference:

Yang Z, et al. Screening with a novel cell-based assay for TAZ activators identifies a compound that enhances myogenesis in C2C12 cells and facilitates muscle repair in a muscle injury model. Mol Cell Biol. 2014;34(9):1607-1621.

Zou R, et al. Inflammation. 2017;40(1):100-105.