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

• Published in: Journal of medicinal chemistry Vol. 64; no. 9; pp. 5689 - 5709
• Main Authors: Kawagoe, Fumihiro, Mendoza, Aileen, Hayata, Yuki, Asano, Lisa, Kotake, Kenjiro, Mototani, Sayuri, Kawamura, Satoshi, Kurosaki, Shigeyuki, Akagi, Yusuke, Takemoto, Yasushi, Nagasawa, Kazuo, Nakagawa, Hayato, Uesugi, Motonari, Kittaka, Atsushi
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.05.2021; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; ACTIVATION; LIPID-METABOLISM; PHOSPHORIC-ACID; PATHWAY; SIDE-CHAIN; ESTERS; BONE; ANTAGONISTS; D ANALOGS; 1-ALPHA,25-DIHYDROXYVITAMIN D-3
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c02179

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.