Therapeutic Potential of a Novel Vitamin D<sub>3</sub> Oxime Analogue, VD1-6, with CYP24A1 Enzyme Inhibitory Activity and Negligible Vitamin D Receptor Binding
Ali K. Alshabrawy,
Yingjie Cui,
Cyan Sylvester,
Dongqing Yang,
Emilio S. Petito,
Kate R. Barratt,
Rebecca K. Sawyer,
Jessica K. Heatlie,
Ruhi Polara,
Matthew J. Sykes,
Gerald J. Atkins,
Shane M. Hickey,
Michael D. Wiese,
Andrea M. Stringer,
Zhaopeng Liu,
Paul H. Anderson
Affiliations
Ali K. Alshabrawy
UniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, Australia
Yingjie Cui
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
Cyan Sylvester
UniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, Australia
Dongqing Yang
Centre for Orthopaedic and Trauma Research, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
Emilio S. Petito
UniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, Australia
Kate R. Barratt
UniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, Australia
Rebecca K. Sawyer
UniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, Australia
Jessica K. Heatlie
UniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, Australia
Ruhi Polara
UniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, Australia
Matthew J. Sykes
UniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, Australia
Gerald J. Atkins
Centre for Orthopaedic and Trauma Research, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia
Shane M. Hickey
UniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, Australia
Michael D. Wiese
UniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, Australia
Andrea M. Stringer
UniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, Australia
Zhaopeng Liu
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
Paul H. Anderson
UniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, Australia
The regulation of vitamin D3 actions in humans occurs mainly through the Cytochrome P450 24-hydroxylase (CYP24A1) enzyme activity. CYP24A1 hydroxylates both 25-hydroxycholecalciferol (25(OH)D3) and 1,25-dihydroxycholecalciferol (1,25(OH)2D3), which is the first step of vitamin D catabolism. An abnormal status of the upregulation of CYP24A1 occurs in many diseases, including chronic kidney disease (CKD). CYP24A1 upregulation in CKD and diminished activation of vitamin D3 contribute to secondary hyperparathyroidism (SHPT), progressive bone deterioration, and soft tissue and cardiovascular calcification. Previous studies have indicated that CYP24A1 inhibition may be an effective strategy to increase endogenous vitamin D activity and decrease SHPT. This study has designed and synthesized a novel C-24 O-methyloxime analogue of vitamin D3 (VD1-6) to have specific CYP24A1 inhibitory properties. VD1-6 did not bind to the vitamin D receptor (VDR) in concentrations up to 10−7 M, assessed by a VDR binding assay. The absence of VDR binding by VD1-6 was confirmed in human embryonic kidney HEK293T cultures through the lack of CYP24A1 induction. However, in silico docking experiments demonstrated that VD1-6 was predicted to have superior binding to CYP24A1, when compared to that of 1,25(OH)2D3. The inhibition of CYP24A1 by VD1-6 was also evident by the synergistic potentiation of 1,25(OH)2D3-mediated transcription and reduced 1,25(OH)2D3 catabolism over 24 h. A further indication of CYP24A1 inhibition by VD1-6 was the reduced accumulation of the 24,25(OH)D3, the first metabolite of 25(OH)D catabolism by CYP24A1. Our findings suggest the potent CYP24A1 inhibitory properties of VD1-6 and its potential for testing as an alternative therapeutic candidate for treating SHPT.
