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ZK168281, a 25-carboxylic ester derivative of 1α,25(OH)2D3, is a novel, potent and pure VDR antagonist with a Kd value of 0.1 nM. ZK168281 is an effective inhibitor of the coactivator (CoA) interaction of its receptor.
ZK168281 (CAS 186371-96-0) is a 25-carboxylic ester 1α,25(OH)2D3 analog and a pure antagonist of the vitamin D receptor (VDR) with a Kd of 0.1 nM. Molecular formula C32H46O5, MW 510.70. ZK168281 is an effective inhibitor of the coactivator (CoA) interaction of its receptor. The VDR is a nuclear hormone receptor that regulates calcium homeostasis, bone metabolism, and cell differentiation. ZK168281 is used for research into vitamin D signaling and its role in cancer and immune function.
| Targets |
The primary target is the vitamin D receptor (VDR). ZK168281 binds to VDR with high affinity (Kd 0.1 nM) and acts as a pure antagonist, inhibiting the interaction of VDR with coactivator proteins. This blocks VDR-mediated gene transcription. The compound is used to study the role of VDR in various biological processes without the confounding effects of agonist activity.
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| ln Vitro |
ZK168281, by virtue of its capacity to attract co-repressor (CoR) proteins, is a more potent constitutive androstenone (CAR) inverse agonist of androstanol. This connection takes place mostly through a salt bridge in helix 4 of the nuclear receptor (NR) between the conserved lysine and the CoR, but direct contact with CoR residues also stabilizes helix 12. Helix 12's fixing in the rigorously antagonistic/narrowly resistive conformation inhibits the C-terminus's energetically unfavorable free gravitation [1].
In vitro activity is evaluated through VDR binding assays. The binding affinity of ZK168281 to VDR is measured using radioligand binding assays, yielding a Kd of 0.1 nM. The compound's ability to inhibit coactivator recruitment to VDR is assessed using TR-FRET or mammalian two-hybrid assays. Its effect on VDR target gene expression is measured by quantitative RT-PCR. |
| ln Vivo |
In vivo activity is manifested through the biological effects of VDR antagonism. In animal models, ZK168281 inhibits VDR-mediated calcium absorption and bone mineralization. It is used to study the role of VDR in cancer, immune function, and skin differentiation. The compound's pharmacokinetic properties are evaluated.
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| Enzyme Assay |
The non-cellular binding assay involves measuring the binding of ZK168281 to VDR using fluorescence polarization or radioligand binding assays. The Kd value (0.1 nM) is determined. The compound's ability to inhibit coactivator peptide recruitment to VDR is assessed using TR-FRET assays.
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| Cell Assay |
Cell-based assays involve treating VDR-expressing cells (e.g., HEK293-VDR, keratinocytes) with ZK168281 at varying concentrations. VDR target gene expression (e.g., CYP24A1) is assessed by quantitative RT-PCR. Cell proliferation and differentiation are measured by MTT assay and differentiation markers.
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| Animal Protocol |
In vivo animal experiments involve administering ZK168281 to rodents via intraperitoneal or oral routes. Doses range from 0.1-10 mg/kg. Serum calcium levels are measured to assess VDR antagonism. Bone mineral density is measured by DXA. The compound's effect on immune function is assessed by measuring cytokine production.
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| References | |
| Additional Infomation |
ZK 168281 is a type of vitamin D.
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| Molecular Formula |
C₃₂H₄₆O₅
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| Molecular Weight |
510.70
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| Exact Mass |
510.335
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| CAS # |
186371-96-0
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| PubChem CID |
9806383
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| Appearance |
White to off-white solid powder
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| Density |
1.151g/cm3
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| Boiling Point |
652.937ºC at 760 mmHg
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| Flash Point |
204.377ºC
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| Vapour Pressure |
0mmHg at 25°C
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| Index of Refraction |
1.578
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| LogP |
5.58
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
37
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| Complexity |
983
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| Defined Atom Stereocenter Count |
7
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| SMILES |
CCOC(=O)/C=C/C1(CC1)[C@@H](/C=C/[C@@H](C)[C@H]2CC[C@@H]\3[C@@]2(CCC/C3=C\C=C/4\C[C@H](C[C@@H](C4=C)O)O)C)O
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| InChi Key |
FUDAEUIGIJZUAY-UMIRZPQISA-N
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| InChi Code |
InChI=1S/C32H46O5/c1-5-37-30(36)14-16-32(17-18-32)29(35)13-8-21(2)26-11-12-27-23(7-6-15-31(26,27)4)9-10-24-19-25(33)20-28(34)22(24)3/h8-10,13-14,16,21,25-29,33-35H,3,5-7,11-12,15,17-20H2,1-2,4H3/b13-8+,16-14+,23-9+,24-10-/t21-,25-,26-,27+,28+,29-,31-/m1/s1
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| Chemical Name |
ethyl (E)-3-[1-[(E,1R,4R)-4-[(1R,3aS,4E,7aR)-4-[(2Z)-2-[(3S,5R)-3,5-dihydroxy-2-methylidenecyclohexylidene]ethylidene]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-1-yl]-1-hydroxypent-2-enyl]cyclopropyl]prop-2-enoate
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~195.81 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9581 mL | 9.7905 mL | 19.5810 mL | |
| 5 mM | 0.3916 mL | 1.9581 mL | 3.9162 mL | |
| 10 mM | 0.1958 mL | 0.9790 mL | 1.9581 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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