Carborane based vitamin D analogs for the treatment of rare disorder induced by hypervitaminosis D – CarBAV

The bioactive vitamin D (1,25D3) is a key regulator of calcium homeostasis. High circulating levels of vitamin D (calcitriosis) lead to hypercalcemia, and are a hallmark of several rare refractory pediatric disorders including idiopathic infantile hypercalcemia type I (IIH1). IIH1 is induced by loss-of-function variants in CYP24A1, encoding a 24-hydroxylase, the main 1,25D3 catabolic enzyme. Current treatments are poorly efficient and greatly impact the development of children. Therefore, there is an urgent need to develop new therapies.

Vitamin D elicits its effect by binding to the Vitamin D Receptor (VDR), a member of the nuclear receptor superfamily. Through a collaborative effort with chemists, we designed five analogs with various carborane-based side chains, and our preliminary results indicate that they are VDR ligands with antagonistic activities, with at least two promising therapeutic options for 1,25D3-induced hypercalcemia.

CarBAV is a pluridisciplinary and translational project on rare diseases combining structural biology, physiology, pathophysiology, pharmacology, and human and mouse preclinical models. This project is led by Natacha Rochel (Team 1) and Gilles Laverny (Team 2), experts in VDR conformational studies and in the use of 1,25D3 analogs as therapy for refractory diseases, respectively. It aims to i) characterize the activities of carborane-based analogs to identify those that bind to VDR, inhibit 1,25D3-induced gene expression, but devoid of VDR agonistic activities, ii) identify the underlying molecular mechanisms, iii) as well as their potency and safety for the treatment of 1,25D3-induced hypercalcemia in relevant preclinical models. To achieve these objectives, CarBaV will use hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS), a method of choice that allow to show that complexes between VDR and ligands with similar structures, as observed by X-ray crystallography, could have different structural dynamics, and, in fine, different selective effects on transcriptional regulation. In addition, the effects of these compounds will be determined in skin-derived fibroblasts obtained from an IIH1 patient, and in genetically engineered mouse model bearing homozygous Cyp24a1 null alleles.

In addition to a better understanding of VDR structure-function-dynamics involved in ligand recognition and on the mechanisms underlying VDR-induced calcium homeostasis, the results gained will be instrumental for the development and the patenting of this new class of drug candidates for therapeutic intervention and care of patients with refractory rare and orphan pediatric diseases induced by acute or chronic high circulating 1,25D3 levels.