Synonym
CCG1423; CCG-1423; CCG 1423.
IUPAC/Chemical Name
N-((1-((4-chlorophenyl)amino)-1-oxopropan-2-yl)oxy)-3,5-bis(trifluoromethyl)benzamide
InChi Key
DSMXVSGJIDFLKP-UHFFFAOYSA-N
InChi Code
InChI=1S/C18H13ClF6N2O3/c1-9(15(28)26-14-4-2-13(19)3-5-14)30-27-16(29)10-6-11(17(20,21)22)8-12(7-10)18(23,24)25/h2-9H,1H3,(H,26,28)(H,27,29)
SMILES Code
O=C(NOC(C)C(NC1=CC=C(Cl)C=C1)=O)C2=CC(C(F)(F)F)=CC(C(F)(F)F)=C2
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, 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:
CCG-1423 is an inhibitor of RhoA/C-mediated gene transcription.
In vitro activity:
Fluorescence staining showed that MLK1 inhibition by CCG-1423 (Figure 3B) significantly downregulated ROS (reactive oxygen species) production in F4/80+ macrophages after IRI (ischemia-reperfusion injury). In response to hypoxia-reoxygenation (H/R), there was augmented occupancy of MKL1 on the proximal Nox gene promoters but not on the Gapdh promoters in cultured macrophages (RAW264.7) as demonstrated by ChIP assay (Figure 3C), indicating that MKL1 might directly regulate NOX gene transactivation. Reporter assay confirmed that overexpression of MKL1 dose-dependently activated promoter activities of NOX genes (Figure IVA in the online-only Data Supplement). In contrast, depletion of endogenous MKL1 with a short-hairpin RNA plasmid downregulated NOX promoter activities (Figure IVB). CCG-1423 treatment abrogated the induction of Nox messages (Figure 3D) and proteins (Figure 3E) in a dose-dependent manner. In keeping with reduced Nox expression, there was a decrease in intracellular ROS levels in CCG-1423-treated cells as assayed by both DHE and DCFH-DA stainings (Figure 3F) and quantitative luminescence assay (Figure 3G).
Reference: Circulation. 2018 Dec 11;138(24):2820-2836. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.035377?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed&
In vivo activity:
The effect of an MKL1 inhibitor CCG-142330 on IRI was investigated in mice. When the mice were injected peritoneally with CCG-1423 for 3 days before the IR procedure, CCG-1423 injection resulted in a significant reduction of infarct size but did not afford detectable improvements in heart function (Figure I). When the mice were injected daily with CCG-1423 for 2 consecutive weeks before the IR procedure and found that prolonged pretreatment with CCG-1423 not only alleviated myocardial infarction (Figure 1E) but mitigated the loss of heart function (Figure 1F through 1H). This discrepancy in the effectiveness of 2 CCG regimens could be partly explained by the observation that although 2 weeks of CCG injection almost completely blocked the nuclear accumulation of MKL1 in cardiac macrophages compared with the vehicle group, 3 days of injection only marginally altered MKL1 localization (Figure II). Taken together, these data suggest that MKL1 loss of function might attenuate myocardial infarction and help retrieve the loss of heart function after IRI.
Reference: Circulation. 2018 Dec 11;138(24):2820-2836. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.035377?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed&
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMF |
10.0 |
21.99 |
| DMSO |
42.9 |
94.27 |
| DMSO:PBS (pH 7.2) (1:5) |
0.2 |
0.33 |
| Ethanol |
2.1 |
4.68 |
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
454.75
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 |
Formulation protocol:
1. Zabini D, Granton E, Hu Y, Miranda MZ, Weichelt U, Breuils Bonnet S, Bonnet S, Morrell NW, Connelly KA, Provencher S, Ghanim B, Klepetko W, Olschewski A, Kapus A, Kuebler WM. Loss of SMAD3 Promotes Vascular Remodeling in Pulmonary Arterial Hypertension via MRTF Disinhibition. Am J Respir Crit Care Med. 2018 Jan 15;197(2):244-260. doi: 10.1164/rccm.201702-0386OC. Erratum in: Am J Respir Crit Care Med. 2019 Apr 1;199(7):932. PMID: 29095649.
2. Yu L, Yang G, Zhang X, Wang P, Weng X, Yang Y, Li Z, Fang M, Xu Y, Sun A, Ge J. Megakaryocytic Leukemia 1 Bridges Epigenetic Activation of NADPH Oxidase in Macrophages to Cardiac Ischemia-Reperfusion Injury. Circulation. 2018 Dec 11;138(24):2820-2836. doi: 10.1161/CIRCULATIONAHA.118.035377. PMID: 30018168.
In vitro protocol:
1. Yu L, Yang G, Zhang X, Wang P, Weng X, Yang Y, Li Z, Fang M, Xu Y, Sun A, Ge J. Megakaryocytic Leukemia 1 Bridges Epigenetic Activation of NADPH Oxidase in Macrophages to Cardiac Ischemia-Reperfusion Injury. Circulation. 2018 Dec 11;138(24):2820-2836. doi: 10.1161/CIRCULATIONAHA.118.035377. PMID: 30018168.
In vivo protocol:
1. Zabini D, Granton E, Hu Y, Miranda MZ, Weichelt U, Breuils Bonnet S, Bonnet S, Morrell NW, Connelly KA, Provencher S, Ghanim B, Klepetko W, Olschewski A, Kapus A, Kuebler WM. Loss of SMAD3 Promotes Vascular Remodeling in Pulmonary Arterial Hypertension via MRTF Disinhibition. Am J Respir Crit Care Med. 2018 Jan 15;197(2):244-260. doi: 10.1164/rccm.201702-0386OC. Erratum in: Am J Respir Crit Care Med. 2019 Apr 1;199(7):932. PMID: 29095649.
2. Yu L, Yang G, Zhang X, Wang P, Weng X, Yang Y, Li Z, Fang M, Xu Y, Sun A, Ge J. Megakaryocytic Leukemia 1 Bridges Epigenetic Activation of NADPH Oxidase in Macrophages to Cardiac Ischemia-Reperfusion Injury. Circulation. 2018 Dec 11;138(24):2820-2836. doi: 10.1161/CIRCULATIONAHA.118.035377. PMID: 30018168.
1: Hayashi K, Watanabe B, Nakagawa Y, Minami S, Morita T. RPEL proteins are the molecular targets for CCG-1423, an inhibitor of Rho signaling. PLoS One. 2014 Feb 18;9(2):e89016. doi: 10.1371/journal.pone.0089016. eCollection 2014. PubMed PMID: 24558465; PubMed Central PMCID: PMC3928398.
2: Bell JL, Haak AJ, Wade SM, Sun Y, Neubig RR, Larsen SD. Design and synthesis of tag-free photoprobes for the identification of the molecular target for CCG-1423, a novel inhibitor of the Rho/MKL1/SRF signaling pathway. Beilstein J Org Chem. 2013 May 21;9:966-73. doi: 10.3762/bjoc.9.111. Print 2013. PubMed PMID: 23766813; PubMed Central PMCID: PMC3678708.
3: Evelyn CR, Bell JL, Ryu JG, Wade SM, Kocab A, Harzdorf NL, Showalter HD, Neubig RR, Larsen SD. Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423. Bioorg Med Chem Lett. 2010 Jan 15;20(2):665-72. doi: 10.1016/j.bmcl.2009.11.056. Epub 2009 Nov 18. PubMed PMID: 19963382; PubMed Central PMCID: PMC2818594.
4: Evelyn CR, Wade SM, Wang Q, Wu M, Iñiguez-Lluhà JA, Merajver SD, Neubig RR. CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling. Mol Cancer Ther. 2007 Aug;6(8):2249-60. PubMed PMID: 17699722.
