Name | (1R)-N-[(4-Fluorophenyl)methyl]-2,3-dihydro-5-[[(methylamino)carbonyl]amino]-2',4'-dioxo-N-[(1S)-2,2,2-trifluoro-1-methylethyl]spiro[1H-indene-1,5'-oxazolidine]-3'-acetamide |
Synonyms | A485 A 485 A-485 A-486 1889279-16-6 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 (1R)-N-[(4-Fluorophenyl)methyl]-2,3-dihydro-5-[[(methylamino)carbonyl]amino]-2',4'-dioxo-N-[(1S)-2,2,2-trifluoro-1-methylethyl]spiro[1H-indene-1,5'-oxazolidine]-3'-acetamide Spiro[1H-indene-1,5'-oxazolidine]-3'-acetamide, N-[(4-fluorophenyl)methyl]-2,3-dihydro-5-[[(methylamino)carbonyl]amino]-2',4'-dioxo-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-, (1R)- |
CAS | 1889279-16-6 |
Molecular Formula | C25H24F4N4O5 |
Molar Mass | 536.48 |
Density | 1.46±0.1 g/cm3(Predicted) |
Solubility | Soluble in DMSO |
pKa | 14.07±0.46(Predicted) |
Storage Condition | 2-8°C |
Physical and Chemical Properties | Bioactive A- 485 is an effective, selective and drug-like p300/CBP catalytic inhibitor with IC50 value of 0.06 μM for p300 HAT. Compared with BET bromine region protein and other non-epigenetic targets larger than 150, it is more selective for p300/CBP. |
Use | A-485 is a potent, selective and drug-like p300/CBP catalytic inhibitor with an IC50 of 0.06 μM for p300 HAT. It is selective over BET bromodomain proteins and >150 non-epigenetic targets. |
In vitro study | A- 485 is A competitive p300/CBP catalytic inhibitor of acetyl-CoA. A- 485 selectively inhibits the proliferation of lineage-specific tumor cells, including several hematologic malignancies, androgen receptor-positive prostate cancer. In androgen-sensitive and castration-resistant stages of prostate cancer, A- 485 inhibit the transcriptional programming of the androgen receptor. A- 485 inhibited activity by p300-BHC(bromodomain-HAT-C/H3,IC50 = 9.8 nM) and CBP-BHC(IC50 = 2.6 nM). A- 485 had no inhibitory effect on PCAF, HAT1, MYST3, MYST4, TIP60 and GCN5L2 at A concentration of 10 μm, it was more selective for p300/CBP than other BET bromodomain proteins, which was more than 150 times higher than that for non-epigenetic punctuation. At 10 μm, A- 485 only binds significantly (>90%) to dopamine and the serotonin transporter, with moderate inhibition of Plk3 (IC50=2.7 μm). However, since A- 485 has no significant exposure in the brain, it is unlikely that it will regulate these transporters in vivo. In cells, A- 485 was more selective for p300/CBP than other HATs and methyltransferases, which inhibited only H3K27Ac and H3K18Ac. In vitro, A- 485 is metabolized primarily via CYP3A4. A- 485 had moderate inhibition of CYP2C8 and CYP2C9 with IC50 of 0.99 μm and 1.65 μm, respectively, and it had no activity on hERG (IC50>30 μm). |
In vivo study | A- 485 has good ADME (absorption, distribution, metabolism, excretion) properties in the body as well as pharmacokinetic parameters. In a castration-resistant xenograft model, tumor growth was inhibited by A- 485. LuCaP-77 treatment of mice bearing A- 485 CR tumors, A- 485, induced a reduction in the level of c-Myc protein within the tumors and some reduction in body weight. |
Reference Show more | 1. http://www.thesgc.org/chemical-probes/A-4852: 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. |
1mg | 5mg | 10mg | |
---|---|---|---|
1 mM | 1.864 ml | 9.32 ml | 18.64 ml |
5 mM | 0.373 ml | 1.864 ml | 3.728 ml |
10 mM | 0.186 ml | 0.932 ml | 1.864 ml |
5 mM | 0.037 ml | 0.186 ml | 0.373 ml |
Target
Target Value
p300 HAT
0.06 μM
in vitro studies
A-485 is a competitive p300/CBP catalytic inhibitor of acetyl-CoA. A- 485 can selectively inhibit the proliferation of lineage-specific tumor cells, including several hematological malignancies and androgen receptor positive prostate cancer. In androgen-sensitive and castration-refractory prostate cancer, the transcription program of the androgen receptor is A- 485 inhibited. A- 485 inhibited the activity of p300-BHC(bromodomain-HAT-C/H3,IC50 = 9.8 nM) and CBP-BHC(IC50 = 2.6 nM). At a concentration of 10 μM, A- 485 has no inhibitory effect on PCAF, HAT1, MYST3, MYST4, TIP60 and GCN5L2, and is more selective to p300/CBP than other BET bromine region proteins, which is more than 150 times of non-epigenetic punctuation. At 10 μM, A- 485 only had a large binding (>90%) to dopamine and serotonin transporters, with a moderate inhibitory effect on Plk3 (IC50=2.7 μM). However, since A- 485 has no significant exposure in the brain, it is impossible to regulate these transporters in the body. In cells, A- 485 is more selective to p300/CBP than other HATs and methyltransferase, it only inhibits H3K27Ac and H3K18Ac. In vitro, A- 485 is mainly metabolized by CYP3A4. A- 485 has a moderate inhibitory effect on CYP2C8 and CYP2C9, IC50 is 0.99 μM and 1.65 μM, respectively, and it has no activity on hERG (IC50>30 μM).
In vivo studies
A-485 has good ADME (absorption, distribution, metabolism, excretion) characteristics and pharmacokinetic parameters in vivo. A- 485 inhibits tumor growth in a castration-resistant xenograft model. A- 485 administration of mice carrying LuCaP-77 CR tumors can A- 485 induce a decrease in c-Myc protein levels and a certain degree of weight loss in the tumor.