A-485
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MedKoo CAT#: 555116

CAS#: 1889279-16-6

Description: A-485 is a potent and selective HAT inhibitor of p300/CBP in vitro with an IC50 of 10 nM in a p300 TR-FRET assay and 3 nM in a CBP TR-FRET assay with selectivity > 1000-fold over closely related HATs. SPR data indicates potent binding to p300 (KD=15 nM). In PC-3 cells A-485 reduces H3K27ac with IC50 of 73 nM while not affecting H3K9ac levels. Inhibition of cellular proliferation is observed in several cancer cell types, most notably AR+ prostate, multiple myeloma, and NHL. A-486 is a suitable control with 1000-fold higher IC50 in the p300 TR-FRET assay.


Chemical Structure

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A-485
CAS# 1889279-16-6

Theoretical Analysis

MedKoo Cat#: 555116
Name: A-485
CAS#: 1889279-16-6
Chemical Formula: C25H24F4N4O5
Exact Mass: 536.1683
Molecular Weight: 536.4836
Elemental Analysis: C, 55.97; H, 4.51; F, 14.17; N, 10.44; O, 14.91

Price and Availability

Size Price Availability Quantity
10.0mg USD 350.0 2 Weeks
25.0mg USD 750.0 2 Weeks
50.0mg USD 1350.0 2 Weeks
100.0mg USD 2150.0 2 Weeks
200.0mg USD 2950.0 2 Weeks
500.0mg USD 4950.0 2 Weeks
1.0g USD 6950.0 2 Weeks
2.0g USD 9950.0 2 Weeks
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Synonym: A-485; A 485; A485.

IUPAC/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

InChi Key: VRVJKILQRBSEAG-LFPIHBKWSA-N

InChi Code: InChI=1S/C25H24F4N4O5/c1-14(25(27,28)29)32(12-15-3-5-17(26)6-4-15)20(34)13-33-21(35)24(38-23(33)37)10-9-16-11-18(7-8-19(16)24)31-22(36)30-2/h3-8,11,14H,9-10,12-13H2,1-2H3,(H2,30,31,36)/t14-,24+/m0/s1

SMILES Code: 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

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Product Data:

Biological target: A-485 is a catalytic inhibitor of p300/CBP with IC50s of 9.8 nM and 2.6 nM for p300 and CBP histone acetyltransferase (HAT), respectively.
In vitro activity: Consistent with immunoblotting data (Figure 4), A-485 reduces overall H3K27ac peak intensity in MCF-7 cells (Figure 5A,B). In analyzing the ChIP-seq dataset, this study divided the H3K27ac peaks into four groups (peak types): All Peaks (AP, all detected peaks), Lost Peaks (LP, DMSO unique peaks), Shared Peaks (SP, peaks detected in both DMSO and A-485), and Gained Peaks (GP, A-485 unique peaks) (Figure 5A). In total, 36,352 H3K27ac peaks are detected, among which the number of LPs and SPs is similar, while there are fewer GPs (~8000). A-485 markedly reduces H3K27ac peak intensity in LPs but only has a small effect on SPs (Figure 5B). Reference: Cancers (Basel). 2021 Jun; 13(11): 2799. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200112/
In vivo activity: To investigate the in vivo metabolic properties of A-485, 8-week-old C57BL/6 mice fed with NCD were intraperitoneally administrated with A-485 (20 mg · kg−1 · day−1) for 1 week. A-485-administered mice displayed significantly lower body weight compared with vehicle-administered mice after treatment for 3 days (Fig. 1a). However, food intake was comparable between vehicle- and A-485-administered mice (Fig. S1a). No significant changes were observed for the oxygen consumption (VO2), carbon dioxide (VCO2) production, and respiratory exchange ratios (RER) in mice after A-485 administration (Fig. S1b–d). A-485 decreased total fat mass by ~14%, without affecting total lean mass (Fig. 1b, c). These results indicate that A-485-induced weight loss is attributable to decreased fat mass. Reference: Cell Death Dis. 2020 Sep; 11(9): 745. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486386/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 97.41 181.57
DMF 10.0 18.64
Ethanol 57.88 107.89
Ethanol:PBS (pH 7.2) (1:3) 0.25 0.47

Preparing Stock Solutions

The following data is based on the product molecular weight 536.4836 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Waddell A, Mahmud I, Ding H, Huo Z, Liao D. Pharmacological Inhibition of CBP/p300 Blocks Estrogen Receptor Alpha (ERα) Function through Suppressing Enhancer H3K27 Acetylation in Luminal Breast Cancer. Cancers (Basel). 2021 Jun 4;13(11):2799. doi: 10.3390/cancers13112799. PMID: 34199844; PMCID: PMC8200112. 2. Zhang L, Sheng C, Zhou F, Zhu K, Wang S, Liu Q, Yuan M, Xu Z, Liu Y, Lu J, Liu J, Zhou L, Wang X. CBP/p300 HAT maintains the gene network critical for β cell identity and functional maturity. Cell Death Dis. 2021 May 12;12(5):476. doi: 10.1038/s41419-021-03761-1. PMID: 33980820; PMCID: PMC8116341. 3. Huo S, Liu X, Zhang S, Lyu Z, Zhang J, Wang Y, Nie B, Yue B. p300/CBP inhibitor A-485 inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss. Int Immunopharmacol. 2021 May;94:107458. doi: 10.1016/j.intimp.2021.107458. Epub 2021 Feb 21. PMID: 33626422. 4. Zhou F, Liu Q, Zhang L, Zhu Q, Wang S, Zhu K, Deng R, Liu Y, Yuan G, Wang X, Zhou L. Selective inhibition of CBP/p300 HAT by A-485 results in suppression of lipogenesis and hepatic gluconeogenesis. Cell Death Dis. 2020 Sep 11;11(9):745. doi: 10.1038/s41419-020-02960-6. PMID: 32917859; PMCID: PMC7486386.
In vitro protocol: 1. Waddell A, Mahmud I, Ding H, Huo Z, Liao D. Pharmacological Inhibition of CBP/p300 Blocks Estrogen Receptor Alpha (ERα) Function through Suppressing Enhancer H3K27 Acetylation in Luminal Breast Cancer. Cancers (Basel). 2021 Jun 4;13(11):2799. doi: 10.3390/cancers13112799. PMID: 34199844; PMCID: PMC8200112. 2. Zhang L, Sheng C, Zhou F, Zhu K, Wang S, Liu Q, Yuan M, Xu Z, Liu Y, Lu J, Liu J, Zhou L, Wang X. CBP/p300 HAT maintains the gene network critical for β cell identity and functional maturity. Cell Death Dis. 2021 May 12;12(5):476. doi: 10.1038/s41419-021-03761-1. PMID: 33980820; PMCID: PMC8116341.
In vivo protocol: 1. Huo S, Liu X, Zhang S, Lyu Z, Zhang J, Wang Y, Nie B, Yue B. p300/CBP inhibitor A-485 inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss. Int Immunopharmacol. 2021 May;94:107458. doi: 10.1016/j.intimp.2021.107458. Epub 2021 Feb 21. PMID: 33626422. 2. Zhou F, Liu Q, Zhang L, Zhu Q, Wang S, Zhu K, Deng R, Liu Y, Yuan G, Wang X, Zhou L. Selective inhibition of CBP/p300 HAT by A-485 results in suppression of lipogenesis and hepatic gluconeogenesis. Cell Death Dis. 2020 Sep 11;11(9):745. doi: 10.1038/s41419-020-02960-6. PMID: 32917859; PMCID: PMC7486386.

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1. http://www.thesgc.org/chemical-probes/A-485

2: Lasko LM, Jakob CG, Edalji RP, Qiu W, Montgomery D, Digiammarino EL, Hansen TM, Risi RM, Frey R, Manaves V, Shaw B, Algire M, Hessler P, Lam LT, Uziel T, Faivre E, Ferguson D, Buchanan FG, Martin RL, Torrent M, Chiang GG, Karukurichi K, Langston JW, Weinert BT, Choudhary C, de Vries P, Van Drie JH, McElligott D, Kesicki E, Marmorstein R, Sun C, Cole PA, Rosenberg SH, Michaelides MR, Lai A, Bromberg KD. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature. 2017 Oct 5;550(7674):128-132. doi: 10.1038/nature24028. Epub 2017 Sep 27. PubMed PMID: 28953875.

A-485

10.0mg / USD 350.0


Additional Information

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. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.