1 research outputs found
Wnt Inhibition Correlates with Human Embryonic Stem Cell Cardiomyogenesis: A Structure–Activity Relationship Study Based on Inhibitors for the Wnt Response
Human embryonic stem cell-based high-content screening
of 550 known
signal transduction modulators showed that one “lead”
(<b>1</b>, a recently described inhibitor of the proteolytic
degradation of Axin) stimulated cardiomyogenesis. Because Axin controls
canonical Wnt signaling, we conducted an investigation to determine
whether the cardiogenic activity of <b>1</b> is Wnt-dependent,
and we developed a structure–activity relationship to optimize
the cardiogenic properties of <b>1</b>. We prepared analogues
with a range of potencies (low nanomolar to inactive) for Wnt/β-catenin
inhibition and for cardiogenic induction. Both functional activities
correlated positively (<i>r</i><sup>2</sup> = 0.72). The
optimal compounds induced cardiogenesis 1.5-fold greater than <b>1</b> at 30-fold lower concentrations. In contrast, no correlation
was observed for cardiogenesis and modulation of transforming growth
factor β (TGFβ)/Smad signaling that prominently influences
cardiogenesis. Taken together, these data show that Wnt signaling
inhibition is essential for cardiogenic activity and that the pathway
can be targeted for the design of druglike cardiogenic molecules