Structural analysis and biological activities of BXL0124, a gemini analog of vitamin D

Abstract

Gemini analogs of calcitriol, characterized by the extension of the C21-methyl group of calcitriol with a second chain, act as agonists of the vitamin D receptor (VDR). This second side chain of gemini is accommodated in a new cavity inside the VDR created by the structural rearrangement of the protein core. The resulting conformational change preserves the active state of the receptor and bestows gemini compounds with biological activities that exceed those of calcitriol. Of particular interest are gemini’s anti-cancer properties, and in this study we demonstrate anti-proliferative and tumor-reducing abilities of BXL0124 and BXL0097, differing only by the presence or absence, respectively, of the methylene group on the A ring. BXL0124 acts as a more potent VDR agonist than its 19-nor counterpart by activating VDR-mediated transcription at lower concentrations. In a similar manner, BXL0124 is more active than BXL0097 in growth inhibition of breast cancer cells and reduction of tumor volume. Structural comparisons of BXL0097 and BXL0124, as their VDR complexes, explain the elevated activity of the latter.

Analysis of the Transcriptome: Regulation of Cancer Stemness in Breast Ductal Carcinoma In Situ by Vitamin D Compounds

“…Reagents and cell culture 1a25(OH) 2 D 3 and a Gemini vitamin D analog [BXL0124; 1a,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4trideuterobutyl)-23-yne-26,27-hexafluoro-cholecalciferol, >95% purity] were provided by BioXCell, Inc. (17). Vitamin D compounds were dissolved in DMSO.…”

“…These compounds reduce in vitro mammosphere formation and in vivo tumorigenesis, although the molecular mechanisms of these effects are not known. BXL0124 is an analog of calcitriol (1a25(OH) 2 D 3 ) modified with an additional side chain at C21methyl group, endowing it with more biological activity at lower concentrations without causing hypercalcemia, a limiting side effect of vitamin D (17). BXL0124 also inhibits MCF10DCIS xenograft tumorigenesis more potently than 1a25(OH) 2 D 3 , apparently through the similar mechanism of suppressing CSCs (18).…”

“…Three independent experiments were performed. Cycle numbers for genes related to CYP24A1, KRTA6A, KRTA5, EMP1, S100A4, LCN2, NGFR, PPP1R1B, AGR2, GDF15, CAPN6, and IGFBP5 are35,30,17,22,23,21,21,24,23,23,21, and 34, respectively ( Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P < 0.001). FPM, fragments per million.…”

Development of novel Gemini-cholesterol analogues for retinoid-related orphan receptors

“…The hydroxylated side chain points towards H11, occupying the parental pocket, regardless of the Gemini configuration at C20, as previously observed for vitamin D Gemini ligands. 32 However, the hydroxylated side chain is more loosely positioned as seen from the weak electron density map for some atoms of this side chain (ESI Fig. 1B †) and adopts an alternative more extended conformation resulting in a distance of 16.6 Å between the 25-OH group and the 3-OH group in compound 4, compared to 13.9 Å in 25HC.…”

Vitamin D and Its Synthetic Analogs

“…These compounds have an unsaturated D-ring between C-16 and C-17 and a cyclopropyl group located at C-20. The structural diversity on the side-chain covered triple CC bonds (138−144), double CC bonds (145−147) and single CC bonds (148 and 149) together with the A-ring covered 1α,3β-dihydroxy (138,143,146, and 149), 19-nor (139,142,145, and 148), 3-deoxy-1α-hydroxy (141), and 1α-fluor-3β-hydroxy (140 and 144). The anti-inflammatory properties of these compounds were studied via analyzing the inhibition of the secretion of the cytokines interferon-γ (IFNG) and tumor necrosis factor (TNF).…”