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

Abstract 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...

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Autores principales: Santosh A. Khedkar, Mohammed A. Samad, Sangita Choudhury, Ji Yoo Lee, Dongsheng Zhang, Ravi I. Thadhani, S. Ananth Karumanchi, Alan C. Rigby, Peter M. Kang
Formato: article
Lenguaje:EN
Publicado: Nature Portfolio 2017
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Acceso en línea:https://doaj.org/article/853bea727f7e4295a02ec950760e473a
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Sumario:Abstract 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 D3 (1,25-D3 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.