A Small-Molecule SLD1121 Activates Wnt/β-Catenin Signaling and Promotes Hair Growth via Targeting the Wnt Coreceptor LRP6

LRP6 is a Wnt coreceptor and plays a key role in Wnt signal transduction. However, the molecular mechanism of LRP6 action in the Wnt signaling cascade has not been fully elucidated. In this study, a small molecule compound SLD1121 is synthesized and identified as a novel agonist of the Wnt/β-catenin signaling pathway. Our results showed that SLD1121 could enhance Wnt signaling through targeting LRP6. SLD1121 interacted with the intracellular domain of LRP6, stabilized LRP6, and accelerated its nuclear translocation. Moreover, SLD1121 promoted the association of LRP6 with β-catenin, or TCF4 or LEF1 in the nucleus, resulting in the expression of Wnt regulatory genes and stemness-associated genes. In a hair regeneration model of C57BL/6J mice, SLD1121 induced the transition of hair follicles from the telogen to anagen phase in the mouse hair growth cycle through the activation of Wnt/β-catenin signaling, resulting in enhanced hair growth of mice. Collectively, our results provide a novel insight into the molecular mechanism for the LRP6-mediated Wnt signaling cascade. By targeting LRP6, SLD1121 has the potential to be used as a therapeutic agent for alopecia.

Alopecia; LRP6; SLD1121; Wnt/β-catenin signaling.