WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H531658
CAS#: 1443437-74-8
Description: CCG-203971 is an inhibitor of SRE activation in the prostate cancer cell line PC-3 (IC50 = 6.4 μM), with 87% inhibition of SRE activation achieved at 100 μM. This compound also inhibits PC-3 cell migration (IC50 = 4.2 μM), as determined by a scratch wound assay
Hodoodo Cat#: H531658
Name: CCG-203971
CAS#: 1443437-74-8
Chemical Formula: C23H21ClN2O3
Exact Mass: 408.12
Molecular Weight: 408.880
Elemental Analysis: C, 67.56; H, 5.18; Cl, 8.67; N, 6.85; O, 11.74
Synonym: CCG-203971; CCG 203971; CCG203971.
IUPAC/Chemical Name: N-(4-chlorophenyl)-1-[3-(furan-2-yl)benzoyl]piperidine-3-carboxamide
InChi Key: HERLZBNILRVHQN-UHFFFAOYSA-N
InChi Code: InChI=1S/C23H21ClN2O3/c24-19-8-10-20(11-9-19)25-22(27)18-6-2-12-26(15-18)23(28)17-5-1-4-16(14-17)21-7-3-13-29-21/h1,3-5,7-11,13-14,18H,2,6,12,15H2,(H,25,27)
SMILES Code: O=C(C1CN(C(C2=CC=CC(C3=CC=CO3)=C2)=O)CCC1)NC4=CC=C(Cl)C=C4
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
More Info:
| Biological target: | CCG-203971 is a second-generation Rho/MRTF/SRF pathway inhibitor. CCG-203971 potently targets RhoA/C-activated SRE-luciferase (IC50 =6.4 μM). CCG-203971 inhibits PC-3 cell migration with an IC50 of 4.2 μM. |
| In vitro activity: | Candidate MRTF/SRF pathway inhibitor, CCG-203971, was tested using a functional three-dimensional fibroblast-populated collagen contraction assay. This assay was chosen as it has been shown to be a good in vitro model to study tissue contraction. CCG-203971 decreased collagen matrix contraction in a concentration-dependent manner but CCG-222740 was five times more potent than CCG-203971 in human conjunctival fibroblasts [IC50 = 5 μM compared to 25 μM] (Fig. 1A and B). These results were confirmed in rabbit conjunctival fibroblasts, where CCG-222740 was similarly more effective at decreasing collagen matrix contraction than CCG-203971 (Fig. 2A and B). In addition, CCG-222740 was less cytotoxic than CCG-203971 with a cell viability of 100% at 10 μM, 88% at 30 μM, and 85% at 100 μM (Fig. 1C). How CCG-222740 and CCG-203971 affect the activity of an SRF reporter gene was also compared in transfected cells. Both compounds showed similar activity, with almost 100% inhibition of baseline reporter activity (Figs 1D and 2E,F). However, examination of endogenous gene expression revealed that CCG-222740 was a more potent inhibitor of expression for two MRTF/SRF target genes classically linked to fibrosis (ACTA2, coding for alpha-smooth muscle actin – αSMA; and CTGF, coding for Connective Tissue Growth Factor) (Fig. 1E–H). CCG-222740 also decreased ACTA2 gene expression to a greater extent than CCG-203971 in rabbit conjunctival fibroblasts (Fig. 2C and D). Reference: Sci Rep. 2017 Mar 31;7(1):518. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/28364121/ |
| In vivo activity: | To determine whether these effects would translate in vivo, CCG-203971 was tested in a bleomycin skin injury model. Because of its modest solubility, bleomycin was administered in 50 μl of DMSO intraperitoneally. Preliminary studies showed that the compound administered in this manner was well tolerated at 100 mg/kg twice a day. Intradermal bleomycin for 2 weeks along with the DMSO control (50 μl i.p.) resulted in marked dermal thickening (P < 0.0001) compared with the PBS+DMSO group, which did not receive bleomycin (Fig. 5, A–B). CCG-203971 treatment strongly and significantly (P < 0.001) suppressed the bleomycin-induced skin thickening in this model (Fig. 5, A–B). Skin collagen amounts, assessed by measurement of hydroxyproline content, showed similar results. Bleomycin injections promoted collagen deposition (P < 0.01) and CCG-203971 was able to block this effect (P < 0.05, Fig. 5C). Reference: J Pharmacol Exp Ther. 2014 Jun;349(3):480-6. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24706986/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 81.0 | 198.10 |
The following data is based on the product molecular weight 408.88 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: | |
| In vitro protocol: | 1. Yu-Wai-Man C, Spencer-Dene B, Lee RMH, Hutchings K, Lisabeth EM, Treisman R, Bailly M, Larsen SD, Neubig RR, Khaw PT. Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis. Sci Rep. 2017 Mar 31;7(1):518. doi: 10.1038/s41598-017-00212-w. PMID: 28364121; PMCID: PMC5428058. 2. Haak AJ, Tsou PS, Amin MA, Ruth JH, Campbell P, Fox DA, Khanna D, Larsen SD, Neubig RR. Targeting the myofibroblast genetic switch: inhibitors of myocardin-related transcription factor/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury. J Pharmacol Exp Ther. 2014 Jun;349(3):480-6. doi: 10.1124/jpet.114.213520. Epub 2014 Apr 4. PMID: 24706986; PMCID: PMC4019321. |
| In vivo protocol: | 1. Haak AJ, Tsou PS, Amin MA, Ruth JH, Campbell P, Fox DA, Khanna D, Larsen SD, Neubig RR. Targeting the myofibroblast genetic switch: inhibitors of myocardin-related transcription factor/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury. J Pharmacol Exp Ther. 2014 Jun;349(3):480-6. doi: 10.1124/jpet.114.213520. Epub 2014 Apr 4. PMID: 24706986; PMCID: PMC4019321. 2. Hutchings KM, Lisabeth EM, Rajeswaran W, Wilson MW, Sorenson RJ, Campbell PL, Ruth JH, Amin A, Tsou PS, Leipprandt JR, Olson SR, Wen B, Zhao T, Sun D, Khanna D, Fox DA, Neubig RR, Larsen SD. Pharmacokinetic optimitzation of CCG-203971: Novel inhibitors of the Rho/MRTF/SRF transcriptional pathway as potential antifibrotic therapeutics for systemic scleroderma. Bioorg Med Chem Lett. 2017 Apr 15;27(8):1744-1749. doi: 10.1016/j.bmcl.2017.02.070. Epub 2017 Mar 10. PMID: 28285914; PMCID: PMC5395305. |
1: Johnson LA, Rodansky ES, Moons DS, Larsen SD, Neubig RR, Higgins PD. Optimisation of Intestinal Fibrosis and Survival in the Mouse S. Typhimurium Model for Anti-fibrotic Drug Discovery and Preclinical Applications. J Crohns Colitis. 2016 Dec 16. pii: jjw210. [Epub ahead of print] PubMed PMID: 27986839.
2: Haak AJ, Appleton KM, Lisabeth EM, Misek SA, Ji Y, Wade SM, Bell JL, Rockwell CE, Airik M, Krook MA, Larsen SD, Verhaegen M, Lawlor ER, Neubig RR. Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma. Mol Cancer Ther. 2017 Jan;16(1):193-204. doi: 10.1158/1535-7163.MCT-16-0482. PubMed PMID: 27837031.
3: Korol A, Taiyab A, West-Mays JA. RhoA/ROCK signaling regulates TGFβ-induced epithelial-mesenchymal transition of lens epithelial cells through MRTF-A. Mol Med. 2016 Sep 29;22. doi: 10.2119/molmed.2016.00041. [Epub ahead of print] PubMed PMID: 27704140; PubMed Central PMCID: PMC5135079.
4: Watanabe B, Minami S, Ishida H, Yoshioka R, Nakagawa Y, Morita T, Hayashi K. Stereospecific Inhibitory Effects of CCG-1423 on the Cellular Events Mediated by Myocardin-Related Transcription Factor A. PLoS One. 2015 Aug 21;10(8):e0136242. doi: 10.1371/journal.pone.0136242. PubMed PMID: 26295164; PubMed Central PMCID: PMC4546662.
5: Sisson TH, Ajayi IO, Subbotina N, Dodi AE, Rodansky ES, Chibucos LN, Kim KK, Keshamouni VG, White ES, Zhou Y, Higgins PD, Larsen SD, Neubig RR, Horowitz JC. Inhibition of myocardin-related transcription factor/serum response factor signaling decreases lung fibrosis and promotes mesenchymal cell apoptosis. Am J Pathol. 2015 Apr;185(4):969-86. doi: 10.1016/j.ajpath.2014.12.005. PubMed PMID: 25681733; PubMed Central PMCID: PMC4380846.
6: Haak AJ, Tsou PS, Amin MA, Ruth JH, Campbell P, Fox DA, Khanna D, Larsen SD, Neubig RR. Targeting the myofibroblast genetic switch: inhibitors of myocardin-related transcription factor/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury. J Pharmacol Exp Ther. 2014 Jun;349(3):480-6. doi: 10.1124/jpet.114.213520. PubMed PMID: 24706986; PubMed Central PMCID: PMC4019321.
7: Johnson LA, Rodansky ES, Haak AJ, Larsen SD, Neubig RR, Higgins PD. Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF-β-induced fibrogenesis in human colonic myofibroblasts. Inflamm Bowel Dis. 2014 Jan;20(1):154-65. doi: 10.1097/01.MIB.0000437615.98881.31. PubMed PMID: 24280883; PubMed Central PMCID: PMC4893808.
8: Bell JL, Haak AJ, Wade SM, Kirchhoff PD, Neubig RR, Larsen SD. Optimization of novel nipecotic bis(amide) inhibitors of the Rho/MKL1/SRF transcriptional pathway as potential anti-metastasis agents. Bioorg Med Chem Lett. 2013 Jul 1;23(13):3826-32. doi: 10.1016/j.bmcl.2013.04.080. PubMed PMID: 23707258; PubMed Central PMCID: PMC3707396.
