Discovery of a Vitamin D Receptor-Silent Vitamin D Derivative That Impairs Sterol Regulatory Element-Binding Protein In Vivo

Vitamin
D3 metabolites inhibit the expression of lipogenic
genes by impairing sterol regulatory element-binding protein (SREBP),
a master transcription factor of lipogenesis, independent of their
canonical activity through a vitamin D receptor (VDR). Herein, we
designed and synthesized a series of vitamin D derivatives to search
for a drug-like small molecule that suppresses the SREBP-induced lipogenesis
without affecting the VDR-controlled calcium homeostasis in vivo.
Evaluation of the derivatives in cultured cells and mice led to the
discovery of VDR-silent SREBP inhibitors and to the development of
KK-052 (50), the first vitamin D-based SREBP inhibitor
that has been demonstrated to mitigate hepatic lipid accumulation
without calcemic action in mice. KK-052 maintained the ability of
25-hydroxyvitamin D3 to induce the degradation of SREBP
but lacked in the VDR-mediated activity. KK-052 serves as a valuable
compound for interrogating SREBP/SCAP in vivo and may represent an
unprecedented translational opportunity of synthetic vitamin D analogues.