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Purity: ≥98%
A-485 (A485) is a potent, drug-like and selective HAT (histone acetyltransferase) inhibitor of p300/CBP with potential antitumor activity. It inhibits p300 and CBP with an IC50 of 10 nM in a p300 TR-FRET assay and 3 nM in a CBP TR-FRET assay. A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products, bi-substrate analogues and the widely used small molecule C646, lack potency or selectivity. A-485 represents a new approach for treating transcriptional activator-driven malignancies and diseases.
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| ln Vitro |
A-485 treatment of prostate cancer PC-3 cells for three hours causes a dose-dependent reduction in H3K27Ac, with a half maximum effective concentration (EC50) of 73 nM. A-485 therapy has no effect on the levels of the proteins p300 or CBP. A-485 shows strong action in the majority of multiple myeloma cell lines, as well as in a minority of acute myeloid leukemia and non-Hodgkin's lymphoma lines, in haematological cancers, where the largest sensitivity is found. In all five prostate cancer cell lines, A-485 causes a similar reduction in H3K27Ac[1].
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| ln Vivo |
Twice daily intraperitoneal injections of A-485 result in 54% tumor growth suppression after 21 days of therapy (P<0.005 compared to vehicle control) after tumors are grown in male SCID mice. Furthermore, a seven-day dose of A-485 causes a reduction in the mRNA levels of MYC and the AR-dependent gene SLC45A3 three hours after the dose, as well as a decrease in the protein level of MYC, suggesting that A-485 inhibits p300-mediated transcriptional activity in vivo. These results are obtained in tumour-bearing animals. On the seventh day, however, the levels of the medication A-485 in the plasma and tumor are lower at 16 hours after dosage compared to 3 hours. After finishing the A-485 dosage regimen, the animals experience a slight 9% reduction in body weight and quickly recover[1].
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| References |
[1]. Lasko LM, et al. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature. 2017 Oct 5;550(7674):128-132
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| Molecular Formula |
C25H24F4N4O5
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|---|---|
| Molecular Weight |
536.4836
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| Exact Mass |
536.1683
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| CAS # |
1889279-16-6
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| Related CAS # |
1889279-16-6
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| SMILES |
O=C(N1CC(N([C@H](C(F)(F)F)C)CC2=CC=C(F)C=C2)=O)[C@@]3(OC1=O)CCC4=CC(NC(NC)=O)=CC=C43
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| Chemical Name |
N-(4-fluorobenzyl)-2-((R)-5-(3-methylureido)-2',4'-dioxo-2,3-dihydrospiro[indene-1,5'-oxazolidin]-3'-yl)-N-((S)-1,1,1-trifluoropropan-2-yl)acetamide
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| Synonyms |
A-485 A 485 A485.
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 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 : ~125 mg/mL (~233.00 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 11 mg/mL (20.50 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.88 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.88 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.08 mg/mL (3.88 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8640 mL | 9.3200 mL | 18.6400 mL | |
| 5 mM | 0.3728 mL | 1.8640 mL | 3.7280 mL | |
| 10 mM | 0.1864 mL | 0.9320 mL | 1.8640 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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