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Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia

Vitamin D regulates many biological processes, but its clinical utility is limited by its hypercalcemic effect. Using a virtual screening platform to search novel chemical probes that activate the vitamin D signaling, we report discovery of novel non-steroidal small-molecule compounds that activate...

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Autores principales: Khedkar, Santosh A., Samad, Mohammed A., Choudhury, Sangita, Lee, Ji Yoo, Zhang, Dongsheng, Thadhani, Ravi I., Karumanchi, S. Ananth, Rigby, Alan C., Kang, Peter M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559458/
https://www.ncbi.nlm.nih.gov/pubmed/28814738
http://dx.doi.org/10.1038/s41598-017-08670-y
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author Khedkar, Santosh A.
Samad, Mohammed A.
Choudhury, Sangita
Lee, Ji Yoo
Zhang, Dongsheng
Thadhani, Ravi I.
Karumanchi, S. Ananth
Rigby, Alan C.
Kang, Peter M.
author_facet Khedkar, Santosh A.
Samad, Mohammed A.
Choudhury, Sangita
Lee, Ji Yoo
Zhang, Dongsheng
Thadhani, Ravi I.
Karumanchi, S. Ananth
Rigby, Alan C.
Kang, Peter M.
author_sort Khedkar, Santosh A.
collection PubMed
description Vitamin D regulates many biological processes, but its clinical utility is limited by its hypercalcemic effect. Using a virtual screening platform to search novel chemical probes that activate the vitamin D signaling, we report discovery of novel non-steroidal small-molecule compounds that activate the vitamin D receptor (VDR), but are devoid of hypercalcemia. A lead compound (known as VDR 4-1) demonstrated potent transcriptional activities in a VDR reporter gene assay, and significantly ameliorated cardiac hypertrophy in cell culture studies and in animal models. VDR 4-1 also effectively suppressed secondary hyperparathyroidism in 1α-hydroxylase knockout mice. In contrast to 1α,25-dihydroxyvitamin D(3) (1,25-D(3) or calcitriol), a naturally occurring VDR agonist, VDR 4-1 therapy even at high doses did not induce hypercalcemia. These findings were accompanied by a lack of upregulation of calcium transport genes in kidney and in the gut providing a mechanism for the lack of hypercalcemia. Furthermore, VDR 4-1 therapy significantly suppressed cardiac hypertrophy and progression to heart failure in both vitamin D deficient and normal mice without inducing significant hypercalcemia. In conclusion, we have identified a unique VDR agonist compound with beneficial effects in mouse models of hyperparathyroidism and heart failure without inducing significant hypercalcemia.
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spelling pubmed-55594582017-08-18 Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia Khedkar, Santosh A. Samad, Mohammed A. Choudhury, Sangita Lee, Ji Yoo Zhang, Dongsheng Thadhani, Ravi I. Karumanchi, S. Ananth Rigby, Alan C. Kang, Peter M. Sci Rep Article Vitamin D regulates many biological processes, but its clinical utility is limited by its hypercalcemic effect. Using a virtual screening platform to search novel chemical probes that activate the vitamin D signaling, we report discovery of novel non-steroidal small-molecule compounds that activate the vitamin D receptor (VDR), but are devoid of hypercalcemia. A lead compound (known as VDR 4-1) demonstrated potent transcriptional activities in a VDR reporter gene assay, and significantly ameliorated cardiac hypertrophy in cell culture studies and in animal models. VDR 4-1 also effectively suppressed secondary hyperparathyroidism in 1α-hydroxylase knockout mice. In contrast to 1α,25-dihydroxyvitamin D(3) (1,25-D(3) or calcitriol), a naturally occurring VDR agonist, VDR 4-1 therapy even at high doses did not induce hypercalcemia. These findings were accompanied by a lack of upregulation of calcium transport genes in kidney and in the gut providing a mechanism for the lack of hypercalcemia. Furthermore, VDR 4-1 therapy significantly suppressed cardiac hypertrophy and progression to heart failure in both vitamin D deficient and normal mice without inducing significant hypercalcemia. In conclusion, we have identified a unique VDR agonist compound with beneficial effects in mouse models of hyperparathyroidism and heart failure without inducing significant hypercalcemia. Nature Publishing Group UK 2017-08-16 /pmc/articles/PMC5559458/ /pubmed/28814738 http://dx.doi.org/10.1038/s41598-017-08670-y Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Khedkar, Santosh A.
Samad, Mohammed A.
Choudhury, Sangita
Lee, Ji Yoo
Zhang, Dongsheng
Thadhani, Ravi I.
Karumanchi, S. Ananth
Rigby, Alan C.
Kang, Peter M.
Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia
title Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia
title_full Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia
title_fullStr Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia
title_full_unstemmed Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia
title_short Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia
title_sort identification of novel non-secosteroidal vitamin d receptor agonists with potent cardioprotective effects and devoid of hypercalcemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559458/
https://www.ncbi.nlm.nih.gov/pubmed/28814738
http://dx.doi.org/10.1038/s41598-017-08670-y
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