Synonym
C646; C-646; C 646.
IUPAC/Chemical Name
(E)-4-(4-((5-(4,5-dimethyl-2-nitrophenyl)furan-2-yl)methylene)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid
InChi Key
HEKJYZZSCQBJGB-XDHOZWIPSA-N
InChi Code
InChI=1S/C24H19N3O6/c1-13-10-20(21(27(31)32)11-14(13)2)22-9-8-18(33-22)12-19-15(3)25-26(23(19)28)17-6-4-16(5-7-17)24(29)30/h4-12H,1-3H3,(H,29,30)/b19-12+
SMILES Code
O=C(O)C1=CC=C(N2N=C(C)/C(C2=O)=C\C3=CC=C(C4=CC(C)=C(C)C=C4[N+]([O-])=O)O3)C=C1
Appearance
Orange to red solid powder
Purity
>98% (Note: this molecule exists as a mixture of cis- and trans- isomers)
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, not in water
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
Biological target:
C646 is a selective and competitive histone acetyltransferase p300 inhibitor with Ki of 400 nM, and is less potent for other acetyltransferases.
In vitro activity:
Given the broad and important effects of p300/CBP on key genes and pathways involved in cell growth, the pharmacologic effects of C646 on 3H-thymidine incorporation were explored at 24h in three melanoma Figure 5A) and three non-small cell lung cancer lines (Figure 5B). We compared the effects of C646 (10 μM) and the peptide-based bisubstrate p300/CBP HAT inhibitor Lys-CoA-Tat (25 μM) and found that both were capable of reducing 3H-thymidine incorporation in several of these human cancer lines to varying degrees (Figure 5A and 5B). Control compounds, C37 and Ac-DDDD-Tat, which lack p300 inhibitory properties, had no effects on 3H-thymidine incorporation as shown in Figure 5A and 5B. In general, reduction of 3H-thymidine incorporation was correlated for Lys-CoA-Tat and C646 among the different cell lines (Figure 5A,B), consistent with a common protein target presumed to be the p300/CBP HAT, although C646 generally showed greater effects at the doses used. For example, the melanoma line WM35 and the lung cancer line H23 were quite susceptible to C646 treatment with Lys-CoA-Tat showing modest inhibitory effects in these cells. Notably, the immortalized murine fibroblast cell line, NIH3T3, was not inhibited by C646 at 20 μM suggesting a differential effect on the malignant cells evaluated (Figure 5C).
Reference: Chem Biol. 2010 May 28;17(5):471-82. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20534345/
In vivo activity:
To examine the role of p300 in the ILPFC during the formation of fear extinction memory, a small-molecule inhibitor specific for C646, or a control compound (C37) was infused into the ILPFC immediately after extinction training (5 CS). Relative to retention control mice (FC-No EXT C37), the 5CS extinction training protocol did not lead to persistent extinction memory in extinction-trained control mice (EXT C37). However, there was a significant reduction in freezing in mice that had received C646 immediately after extinction training (F(3,23) = 4.70; p < 0.05; Dunnett's post hoc test, FC- No EXT C37 vs EXT C646, p < 0.05) (Fig. 3A). During fear acquisition, although all mice learned to freeze in response to the tone relative to the no-shock controls, there was no effect of PLPFC infusion of C646 on memory for cued fear (Fig. 3B). There was also no effect of C646 on fear extinction memory if the compound was infused 6 h after extinction training (Fig. 4A) or if C646 was infused into the PLPFC immediately after fear extinction training (Fig. 4B).
Reference: J Neurosci. 2011 May 18;31(20):7486-91. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21593332/
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
13.0 |
29.19 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
445.43
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.
| 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 |
In vitro protocol:
1. Bowers EM, Yan G, Mukherjee C, Orry A, Wang L, Holbert MA, Crump NT, Hazzalin CA, Liszczak G, Yuan H, Larocca C, Saldanha SA, Abagyan R, Sun Y, Meyers DJ, Marmorstein R, Mahadevan LC, Alani RM, Cole PA. Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor. Chem Biol. 2010 May 28;17(5):471-82. doi: 10.1016/j.chembiol.2010.03.006. PMID: 20534345; PMCID: PMC2884008.
2. Oike T, Komachi M, Ogiwara H, Amornwichet N, Saitoh Y, Torikai K, Kubo N, Nakano T, Kohno T. C646, a selective small molecule inhibitor of histone acetyltransferase p300, radiosensitizes lung cancer cells by enhancing mitotic catastrophe. Radiother Oncol. 2014 May;111(2):222-7. doi: 10.1016/j.radonc.2014.03.015. Epub 2014 Apr 17. PMID: 24746574.
In vivo protocol:
1. Marek R, Coelho CM, Sullivan RK, Baker-Andresen D, Li X, Ratnu V, Dudley KJ, Meyers D, Mukherjee C, Cole PA, Sah P, Bredy TW. Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p300. J Neurosci. 2011 May 18;31(20):7486-91. doi: 10.1523/JNEUROSCI.0133-11.2011. PMID: 21593332; PMCID: PMC3458795.
2. Zhu XY, Huang CS, Li Q, Chang RM, Song ZB, Zou WY, Guo QL. p300 exerts an epigenetic role in chronic neuropathic pain through its acetyltransferase activity in rats following chronic constriction injury (CCI). Mol Pain. 2012 Nov 23;8:84. doi: 10.1186/1744-8069-8-84. PMID: 23176208; PMCID: PMC3558366.
1: Yang Y, Liu K, Liang Y, Chen Y, Chen Y, Gong Y. Histone acetyltransferase
inhibitor C646 reverses epithelial to mesenchymal transition of human peritoneal
mesothelial cells via blocking TGF-β1/Smad3 signaling pathway in vitro. Int J
Clin Exp Pathol. 2015 Mar 1;8(3):2746-54. eCollection 2015. PubMed PMID:
26045780; PubMed Central PMCID: PMC4440089.
2: Oike T, Komachi M, Ogiwara H, Amornwichet N, Saitoh Y, Torikai K, Kubo N,
Nakano T, Kohno T. C646, a selective small molecule inhibitor of histone
acetyltransferase p300, radiosensitizes lung cancer cells by enhancing mitotic
catastrophe. Radiother Oncol. 2014 May;111(2):222-7. doi:
10.1016/j.radonc.2014.03.015. Epub 2014 Apr 17. PubMed PMID: 24746574.
3: Gao XN, Lin J, Ning QY, Gao L, Yao YS, Zhou JH, Li YH, Wang LL, Yu L. A
histone acetyltransferase p300 inhibitor C646 induces cell cycle arrest and
apoptosis selectively in AML1-ETO-positive AML cells. PLoS One. 2013;8(2):e55481.
doi: 10.1371/journal.pone.0055481. Epub 2013 Feb 4. PubMed PMID: 23390536; PubMed
Central PMCID: PMC3563640.
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