AMD 3465

CXCR4 antagonist,potent and selective CAS# 185991-24-6

AMD 3465

Catalog No. BCC5181----Order now to get a substantial discount!

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Chemical structure

AMD 3465

3D structure

Chemical Properties of AMD 3465

Cas No. 185991-24-6 SDF Download SDF
PubChem ID 483559 Appearance Powder
Formula C24H38N6 M.Wt 410.6
Type of Compound N/A Storage Desiccate at -20°C
Synonyms AMD3465,AMD-3465
Solubility Soluble in DMSO
Chemical Name N-(pyridin-2-ylmethyl)-1-[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methanamine
SMILES C1CNCCNCCCN(CCNC1)CC2=CC=C(C=C2)CNCC3=CC=CC=N3
Standard InChIKey CWJJHESJXJQCJA-UHFFFAOYSA-N
Standard InChI InChI=1S/C24H38N6/c1-2-13-29-24(5-1)20-28-19-22-6-8-23(9-7-22)21-30-17-4-12-26-15-14-25-10-3-11-27-16-18-30/h1-2,5-9,13,25-28H,3-4,10-12,14-21H2
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of AMD 3465

DescriptionAMD 3465 is a potent, selective CXCR4 antagonist, and inhibits SDF-1α-ligand binding with Ki of 41.7 nM.In Vitro:The affinity of AMD3465 is 8-fold higher compared with AMD3100, in competition against the radiolabeled monoclonal antibody raised against CXCR4, 12G5. The affinity of AMD3465 is decreased >5000-fold in (D262N)-CXCR4 and 1913-fold in (A175F)-CXCR4. AMD3465 appears to interact with HisVII:-02 at the extracellular end of TM-VII (at the interface to extracellular loop 3) and HisIII:05. Both of these His residues are facing right into the main binding pocket of CXCR4[1]. AMD3465 inhibits 125I-SDF-1α ligand binding to CCRF-CEM cells. AMD3465 inhibits CXCR4 activation as measured by GTP binding with an IC50 of 10.38±1.99 nM, and inhibits SDF-1α mediated calcium flux with an IC50 of 12.07±2.42 nM[2].In Vivo:AMD3465 (5 mg/kg, s.c.) significantly elevates total white blood cells in DBA/2, C57Bl/6 and BALB/c mice between 0.5 and 2 h. AMD3465 significantly increases the specific cell populations in all three strains of mice included neutrophils, lymphocytes, and monocytes[2].

References:
[1]. Rosenkilde MM, et al. Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor. J Biol Chem. 2007 Sep 14;282(37):27354-65. [2]. Bodart V, et al. Pharmacology of AMD3465: a small molecule antagonist of the chemokine receptor CXCR4. Biochem Pharmacol. 2009 Oct 15;78(8):993-1000.

Protocol

Kinase Assay [2]
For the competition binding studies against CXCR4, a concentration range of AMD3465 is incubated for 3 h at 4°C in binding buffer (PBS containing 5 mM MgCl2, 1 mM CaCl2, 0.25% BSA pH 7.4) with 5×105 CCRF-CEM cells and 100 pM 125I-SDF-1α in Millipore DuraporeTM filter plates. Unbound 125I-SDF-1α is removed by washing with cold 50 mM HEPES, 0.5 M NaCl pH 7.4. The competition binding assay against BLT1 is performed on membranes from CHO-S cells expressing recombinant BLT1. The membranes is prepisd by mechanical cell lysis followed by high speed centrifugation, resuspended in 50 mM HEPES, 5 mM MgCl2 buffer and flash frozen. The membrane preparation is incubated with AMD3465 for 1 h at room temperature in an assay mixture containing 50 mM Tris, pH 7.4, 10 mM MgCl2, 10 mM CaCl2, 4 nM LTB4 mixed with 1 nM 3H-LTB4 and 8 μg membrane. The unbound 33H-LTB4 is separated by filtration on Millipore Type GF-C filter plates. The bound radioactivity is counted using a LKB Rackbeta 1209 Liquid Scintillation Counter.

Cell Assay [1]
On the day prior to the experiment, the U87.CD4.CXCR4 transfectants is seeded in 0.1% gelatin-coated 96-well black wall microplates (Costar, Cambridge, MA) at 2×104 cells per well. On the day of the experiment, the cells is loaded with the fluorescent calcium indicator Fluo-3 acetoxymethyl at 4 μM for 45 min at 37°C. After thorough washing with calcium flux assay buffer (Hanks' balanced salt solution with 20 mM Hepes buffer and 0.2% bovine serum albumin, pH 7.4), the cells is preincubated for 15 min at 37°C with AMD3100 or AMD3465 (1 μg/mL) in the same buffer. Then, the intracellular calcium mobilization in response to 2-50 ng/mL CXCL12 is measured at 37°C by monitoring the fluorescence as a function of time simultaneously in all the wells using a Fluorometric Imaging Plate Reader.

Animal Administration [2]
The maximum tolerated dose (MTD) of AMD3465 is determined in mice. AMD3465 is given as a single subcutaneous injection to five male Swiss Webster mice per dose group (5, 10, 20, 50 and 100 mg/kg). Mice is observed for 48 h following administration; evaluations is made of mortality and morbidity, clinical observations, body weight and gross pathology. The pharmacokinetics of AMD3465 in male Swiss Webster mice is determined for a single 25 mg/kg subcutaneous dose. Blood is collected by cardiocentisis from three mice per time point at 0.25, 0.5, 1, 1.5, 2, 4, 8, 12, and 24 h post-administration. Plasma is obtained following centrifugation (3000 rpm, 10 min) and concentrations of AMD3465 in plasma is determined by LC-MS.

References:
[1]. Rosenkilde MM, et al. Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor. J Biol Chem. 2007 Sep 14;282(37):27354-65. [2]. Bodart V, et al. Pharmacology of AMD3465: a small molecule antagonist of the chemokine receptor CXCR4. Biochem Pharmacol. 2009 Oct 15;78(8):993-1000.

AMD 3465 Dilution Calculator

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AMD 3465 Molarity Calculator

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Preparing Stock Solutions of AMD 3465

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.4355 mL 12.1773 mL 24.3546 mL 48.7092 mL 60.8865 mL
5 mM 0.4871 mL 2.4355 mL 4.8709 mL 9.7418 mL 12.1773 mL
10 mM 0.2435 mL 1.2177 mL 2.4355 mL 4.8709 mL 6.0887 mL
50 mM 0.0487 mL 0.2435 mL 0.4871 mL 0.9742 mL 1.2177 mL
100 mM 0.0244 mL 0.1218 mL 0.2435 mL 0.4871 mL 0.6089 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on AMD 3465

IC50: 10.38 ± 1.99 nM for CXCR4 activation as measured by GTP binding

CXCR4 is widely expressed in multiple cell types, and involved in neonatal development, hematopoiesis, and lymphocyte trafficking and homing. Additionally CXCR4 is a co-receptor for HIV. Small molecule antagonists of CXCR4 thus have therapeutic potential. AMD3465 is an N-pyridinylmethylene monocyclam CXCR4 antagonist blocking infection of T-tropic, CXCR4-using HIV.

In vitro: Using the CCRF-CEM T-cell line expressing CXCR4 previous authors have demonstrated that AMD3465 is an antagonist of SDF-1 ligand binding, and inhibits SDF-1 mediated signaling as shown by inhibition of GTP binding, calcium flux, and inhibition of chemotaxis. AMD3465 does not inhibit chemokine-stimulated calcium flux in cells expressing CXCR3, CCR1, CCR2b, CCR4, CCR5 or CCR7, nor does it inhibit binding of LTB4 to its receptor, BLT1 [1].

In vivo: AMD3465 caused leukocytosis when subcutaneously administered in mice and dogs, with peak mobilization occurring between 0.5 and 1.5 h following subcutaneous dosing in mice and with maximum peak plasma concentration of compound preceding peak mobilization in dogs, demonstrating that AMD3465 has the potential to mobilize hematopoietic stem cells. These data demonstrate the therapeutic potential for the CXCR4 antagonist AMD3465 [1].

Clinical trials: Currenlty no clinical data are available.

Reference:
[1] Bodart V, Anastassov V, Darkes MC, Idzan SR, Labrecque J, Lau G, Mosi RM, Neff KS, Nelson KL, Ruzek MC, Patel K, Santucci Z, Scarborough R, Wong RS, Bridger GJ, Macfarland RT, Fricker SP.   Pharmacology of AMD3465: a small molecule antagonist of the chemokine receptor CXCR4. Biochem Pharmacol. 2009;78(8):993-1000.

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References on AMD 3465

Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo.[Pubmed:17234775]

Cancer Res. 2007 Jan 15;67(2):651-8.

The chemokine CXCL12 and its cognate receptor CXCR4 regulate malignant brain tumor growth and are potential chemotherapeutic targets. However, the molecular basis for CXCL12-induced tumor growth remains unclear, and the optimal approach to inhibiting CXCR4 function in cancer is unknown. To develop such a therapeutic approach, we investigated the signaling pathways critical for CXCL12 function in normal and malignant cells. We discovered that CXCL12-dependent tumor growth is dependent upon sustained inhibition of cyclic AMP (cAMP) production, and that the antitumor activity of the specific CXCR4 antagonist AMD 3465 is associated with blocking cAMP suppression. Consistent with these findings, we show that pharmacologic elevation of cAMP with the phosphodiesterase inhibitor Rolipram suppresses tumor cell growth in vitro and, upon oral administration, inhibits intracranial growth in xenograft models of malignant brain tumors with comparable efficacy to AMD 3465. These data indicate that the clinical evaluation of phosphodiesterase inhibitors in the treatment of patients with brain tumors is warranted.

Description

AMD 3465 is a potent, selective CXCR4 antagonist, and inhibits SDF-1α-ligand binding with Ki of 41.7 nM.

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