Studies on two new vitamin D analogs, EB 1089 and KH 1060: Effects on bone resorption and osteoclast recruitment in vitro

Wiberg, Kristina; Ljunghall, Sverker; Binderup, Lise; Ljunggren, Östen

doi:10.1016/s8756-3282(95)00246-4

Cited by 14 publications

(5 citation statements)

References 19 publications

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“…'HIlabelled VD [Peleg et al, 1995;Wiberg et al, 1995; M@rk Hansen et al, 1996al. In particular, for analogues that have higher affinity to VDR than VD, the latter assay may provide misleading results.…”

Section: Zk157202mentioning

confidence: 99%

Potent gene regulatory and antiproliferative activities of 20-methyl analogues of 1,25 dihydroxyvitamin D3

Danielsson¹,

Nayeri²,

Wiesinger³

et al. 1996

J. Cell. Biochem.

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The biological active form of vitamin D3, 1,25-dihydroxyvitamin D3 (VD), regulates cellular growth and differentiation. This provides the hormone with an interesting therapeutic potential. However, hypercalcemia is a side effect, which is caused by VD's classical action, the regulation of calcium homeostasis. This made the need for VD analogues with selectively increased cell regulatory properties. Studies with 20-epi analogues pointed out the importance of the carbon-20 position and led to the development of 20-methyl derivatives of VD. In this report the biological properties of the compounds ZK161422 and ZK157202, which are 20-methyl- and 20-methyl-23-eneanalogues, respectively, have been analyzed in comparison with VD. Both compounds show about 2-fold lower affinity to the VD receptor (VDR) than VD. However, compared to VD, their antiproliferative effect is up to 30-fold higher on human peripheral blood mononuclear cells and even up to 300-fold higher on human breast cancer MCF-7 cells. Whereas the hypercalcemic effect for ZK157202 is also increased 10-fold, ZK161422 has the same calcium-mobilizing potency as VD. Moreover, ZK161422, but not ZK157202, showed preference for gene activation from a promoter carrying a VD response element with a palindromic arrangement of two hexameric receptor binding sites spaced by 9 nucleotides (IP9) rather than for activation from a response element formed by a direct repeat spaced by 3 nucleotides (DR3). This observation supports a model, in which promoter selectivity reflects the selectively increased antiproliferative effect of VD analogues.

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Section: Zk157202mentioning

confidence: 99%

Potent gene regulatory and antiproliferative activities of 20-methyl analogues of 1,25 dihydroxyvitamin D3

Danielsson¹,

Nayeri²,

Wiesinger³

et al. 1996

J. Cell. Biochem.

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Section: Introductionmentioning

confidence: 99%

“…KH1060 also exhibits strong immunosuppressive activity in both in vitro and in vivo studies (4,8,9). Furthermore, KH1060 is more potent than 1,25-(OH)2vitamin D3 in stimulating in vivo and in vitro bone resorption and osteoclast recruitment in murine bone marrow cultures (4,7,10).The differences in biological activity between 1,25-(OH)2vitamin D3 and KH1060 could not be explained by an increased affinity for the vitamin D receptor (VDR) (4, 5, 7). However, the presence of a (functional) VDR is essential for the biological responses of 1,25-(OH)2vitamin D3 and KH1060 (7,11,12).…”

mentioning

confidence: 99%

Conformational change and enhanced stabilization of the vitamin D receptor by the 1,25-dihydroxyvitamin D3 analog KH1060.

Bemd

Pols

Birkenhäger

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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The 1,25-dihydroxyvitamin D3 [1,2vitamin D3] analog KH1060 exerts very potent effects on cell proliferation and cell differentiation via the vitamin D receptor (VDR). However, the activities of KH1060 are not associated with an increased affinity for the VDR. We now show that increased stabilization of the VDR-KH1060 complex could be an explanation for its high potencies. VDR half-life studies performed with cycloheximide-translational blocked rat osteoblast-like ROS 17/2.8 cells demonstrated that, in the absence of ligand, VDR levels rapidly decreased. After 2 hr, less than 10% of the initial VDR level could be measured. In the presence of 1,25-(OH)2vitamin D3, the VDR half-life was 15 hr. After 24 hr, less than 20% of the initial VDR content was detectable, whereas, at this time-point, when the cells were incubated with KH1060 80% of the VDR was still present. Differences in 1,25-(OH)2vitamin D3-and KH1060-induced conformational changes of the VDR could underlie the increased VDR stability. As assessed by limited proteolytic digestion analysis, both 1,25-(OH)2vitamin D3 and KH1060 caused a specific conformational change of the VDR. Compared with 1,25-(OH)2vitamin D3, KH1060 induced a conformational change that led to a far more dramatic protection of the VDR against proteolytic degradation. In conclusion, the altered VDR stability and the possibly underlying change in VDR conformation caused by KH1060 could be an explanation for its enhanced bioactivity.Besides the traditional effects on calcium and phosphate metabolism (1), the effects of 1,25-dihydroxyvitamin D3 [1,25-(OH)2vitamin D3] on cellular differentiation and proliferation and on immunological processes (2) might have relevance for the treatment of hyperproliferative and autoimmune diseases. However, the side effects (hypercalcemia and hypercalciuria) induced by the high doses needed to achieve these effects limit the use of 1,25-(OH)2vitamin D3 in clinical practice. This has prompted the development of new 1,25-(OH)2vitamin D3 analogs with reduced calcemic activity.Previous studies have shown that modifications in the side chain of the 1,25-(OH)2vitamin D3 molecule can lead to far more potent analogs. One of the most potent analogs until now, 20-Epi-22-oxa-24a,26a,27a-tri-homo-1,25-(OH)2vitamin D3 (KH1060) (3), is a strong inhibitor of tumor cell growth (4, 5) and an inducer of cell differentiation (4, 6, 7). KH1060 also exhibits strong immunosuppressive activity in both in vitro and in vivo studies (4,8,9). Furthermore, KH1060 is more potent than 1,25-(OH)2vitamin D3 in stimulating in vivo and in vitro bone resorption and osteoclast recruitment in murine bone marrow cultures (4,7,10).The differences in biological activity between 1,25-(OH)2vitamin D3 and KH1060 could not be explained by an increased affinity for the vitamin D receptor (VDR) (4, 5, 7). However, the presence of a (functional) VDR is essential for the biological responses of 1,25-(OH)2vitamin D3 and KH1060 (7,11,12). It is known that, through binding to the VDR, 1,25-(OH)2vitam...

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“…However, there are some apparent exceptions to this general rule. In fact, selective analogs of vitamin D are significantly more potent than the natural hormone [124][125][126][127], but do not bind the VDR with greater affinity. Moreover, even though the VDR binding is very poor, some compounds exert potent biological effects.…”

Section: Vdr-rxr-vdre Interactions A) Vdr Bindingmentioning

confidence: 99%

“…Very fast [177] Fast [185] Slow [180] 20-epi-1α,25(OH) 2 D 3 KH 1060 EB 1089 0 [223] 0 [193] 3 [193] 130 [115] 130 [115] 30 [127] 10,000 [73] 300,000 [73] 10,000 [73] 200 [73] 130 [73] 31 [73] 50 2,307 323 Fast [223] Fast [179] Slow [178] 16-ene-1α,25(OH) 2 D 3…”

Section: Vdr-rxr-vdre Interactions A) Vdr Bindingmentioning

confidence: 99%

Vitamin D Analogs- Drug Design Based on Proteins Involved in Vitamin D Signal Transduction

Masuda

Jones²

2003

curr drug targets immune endocr metabol disord

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Vitamin D analogs have proven to be very valuable tools for the treatment of calcium-related diseases and certain hyperproliferative conditions such as renal osteodystrophy, psoriasis and cancer. In general, vitamin D analogs exploit the enzymic and receptor machinery of the 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) signal transduction pathway. Key proteins in this cascade include the vitamin D receptor (VDR), the vitamin D-binding protein (DBP) and three cytochrome P450s (CYP27A, CYP27B and CYP24) which effect the synthesis and breakdown of the natural hormone, 1alpha,25(OH)(2)D(3). Analogs have been designed which reduce or enhance the importance of each of these proteins in the signal transduction pathway. Vitamin D prodrugs require one or more steps of activation and overcome congenital or acquired blocks in the 1alpha-hydroxylation step. By far the biggest class of vitamin D analogs are the VDR agonists which directly mimic 1alpha,25(OH)(2)D(3) and trigger protein conformational changes in the receptor which lead to changes in the transcriptional machinery at vitamin D-responsive genes. Other emerging classes of molecules include the VDR antagonists and CYP24 inhibitors which target different events in the cascade. This review assesses the relative importance of each of the proteins of the vitamin D cascade, evaluates the success of these modifications in tailoring drugs in all classes for selected disease states and contemplates future directions for the field.

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Studies on two new vitamin D analogs, EB 1089 and KH 1060: Effects on bone resorption and osteoclast recruitment in vitro

Cited by 14 publications

References 19 publications

Potent gene regulatory and antiproliferative activities of 20-methyl analogues of 1,25 dihydroxyvitamin D3

Potent gene regulatory and antiproliferative activities of 20-methyl analogues of 1,25 dihydroxyvitamin D3

Conformational change and enhanced stabilization of the vitamin D receptor by the 1,25-dihydroxyvitamin D3 analog KH1060.

Vitamin D Analogs- Drug Design Based on Proteins Involved in Vitamin D Signal Transduction

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