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Chemical Structure| 1443437-74-8 Chemical Structure| 1443437-74-8

Structure of CCG-203971
CAS No.: 1443437-74-8

Chemical Structure| 1443437-74-8

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CCG-203971 is a small-molecule inhibitor of the Rho/MRTF/SRF pathway with the IC50 value of 0.64 μM for SRE.L. It inhibits Rho-mediated gene transcription.

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Product Details of CCG-203971

CAS No. :1443437-74-8
Formula : C23H21ClN2O3
M.W : 408.88
SMILES Code : O=C(C1CN(C(C2=CC=CC(C3=CC=CO3)=C2)=O)CCC1)NC4=CC=C(Cl)C=C4
MDL No. :MFCD28166491
InChI Key :HERLZBNILRVHQN-UHFFFAOYSA-N
Pubchem ID :71681561

Safety of CCG-203971

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P301+P312+P330

Related Pathways of CCG-203971

GPCR

Isoform Comparison

Biological Activity

Target
  • Rho-subclass

In Vitro:

Cell Line
Concentration Treated Time Description References
CCL-210 fibroblasts 30 μmol/L 8 hours To assess the effect of CCG-203971 on Fas-mediated apoptosis. Results showed that CCG-203971 significantly enhanced Fas-mediated apoptosis. PMC4380846
IMR-90 fibroblasts 30 μmol/L 16 hours To assess the effect of CCG-203971 on Fas-mediated apoptosis. Results showed that CCG-203971 significantly enhanced Fas-mediated apoptosis. PMC4380846
CCL-210 fibroblasts 30 μmol/L 24 hours To assess the effect of CCG-203971 on TGF-β1-induced fibronectin expression. Results showed that 30 μmol/L CCG-203971 completely abrogated TGF-β1-induced fibronectin deposition. PMC4380846
CCL-210 fibroblasts 30 μmol/L 24 hours To assess the effect of CCG-203971 on TGF-β1-induced α-SMA expression. Results showed that 30 μmol/L CCG-203971 significantly suppressed TGF-β1-mediated α-SMA expression. PMC4380846
IMR-90 fibroblasts 30 μmol/L 24 hours To assess the effect of CCG-203971 on MRTF-A nuclear localization. Results showed that CCG-203971 significantly reduced MRTF-A nuclear localization. PMC4380846
Rat lens epithelial cells 5 μM 48 hours To investigate the effect of CCG-203971 on TGFβ-induced EMT in lens epithelial cells. Results showed that CCG-203971 prevented TGFβ-induced nuclear accumulation of MRTF-A and αSMA expression. PMC5135079
SK-Mel-147 10 μM 72 hours Inhibits cellular migration and invasion, decreases MRTF target gene expression, and causes G1 cell cycle arrest PMC5555736
Human pulmonary artery endothelial cells (HPAECs) 5 mmol/L 72 hours To evaluate the effect of CCG-203971 on PI hypoxia-induced senescence in HPAECs. Results showed that CCG-203971 treatment reduced the number of SA-β-gal positive cells, decreased p16INK4A gene expression and SASP factor concentrations (IL-1, TNF-α, and MCP1), improved HPAEC proliferation, and reduced the proportion of apoptotic cells. PMC10526072
Human colonic fibroblast CCD-18co 1, 3, 10, 17.5, 25 μM 24 to 48 hours CCG-203971 inhibited TGF-β-induced α SMA and collagen I protein expression and repressed the expression of MKL1, MYLK, ACTA2, and col1A1 genes at the transcriptional level. PMC4893808
MCF10A cells 20 μM 16-36 hours Inhibition of the Rho/MRTF/SRF pathway, reducing protrusion formation of MCF10A cells on stiff matrices. PMC9563482
C2C12 mouse myoblasts 20 µM 24 hours To assess the effect of CCG-203971 on cell viability, results showed significant reduction in cell viability at 20 µM concentration. PMC10931493
WI-38 human lung fibroblasts 20 µM 24 hours To assess the effect of CCG-203971 on cell viability, results showed significant reduction in cell viability at 20 µM concentration. PMC10931493

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
C57BL/6 mice Bleomycin-induced lung fibrosis model Intraperitoneal injection 100 mg/kg Twice daily, from day 11 to day 21 To assess the effect of CCG-203971 on lung fibrosis. Results showed that CCG-203971 significantly reduced lung collagen content and promoted myofibroblast apoptosis. PMC4380846
Mice Mammary acinar organoid model In vitro culture 20 μM 16-36 hours Inhibition of the Rho/MRTF/SRF pathway, reducing protrusion formation of mammary acinar organoids on stiff matrices. PMC9563482
CBA/J mice SL1344:CBA/J fibrosis model Oral gavage 100 mg/kg/day Twice daily for 7 days To evaluate the anti-fibrotic efficacy of CCG-203971 in the SL1344:CBA/J fibrosis model. Results showed that CCG-203971 significantly repressed fibrotic genes COL1A1 and IGF-1, as well as inflammatory genes IL-1β and IL-6. PMC5881735
NOD SCID mice Melanoma lung metastasis model Intraperitoneal injection 100 mg/kg Twice daily for 18 days Significantly reduces the number and size of lung metastases, lowering total lung tumor burden PMC5555736
Mice Bleomycin-induced skin fibrosis model Oral gavage 50 mg/kg/day Once daily for 14 days Assessed the preventive effect of CCG-257081 on skin fibrosis, showing significant reduction in skin thickening and collagen content PMC7006939
C57BL/6 J mice AML syngeneic mouse model Intraperitoneal injection 200 μg Once on day 18, and twice per day on days 19 and 20 CCG-203971 inhibits the Rho-MRTF-SRF signaling pathway, enhancing the anti-tumor effects of chemotherapy and suppressing the migration of chemoresistant C1498 cells. PMC7336645
Rats PI hypoxia model Intraperitoneal injection 0.15 mg/kg Once daily for 21 days To evaluate the effect of CCG-203971 on PI hypoxia-induced senescence and pulmonary arterial remodeling in lung tissue. Results showed that CCG-203971 treatment reduced senescence markers (SA-β-gal positive cells, p16INK4A gene expression, and SASP factor concentrations) and improved pulmonary arterial wall thickness, collagen fiber deposition, and smooth muscle hyperplasia. PMC10526072

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

2.45mL

0.49mL

0.24mL

12.23mL

2.45mL

1.22mL

24.46mL

4.89mL

2.45mL

References

[1]Johnson LA, Rodansky ES, et al. 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.

[2]Haak AJ, Appleton KM, et al. Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma. Mol Cancer Ther. 2017 Jan;16(1):193-204.

[3]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

[4]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

[5]Lisabeth EM, Kahl D, Gopallawa I, Haynes SE, Misek SA, Campbell PL, Dexheimer TS, Khanna D, Fox DA, Jin X, Martin BR, Larsen SD, Neubig RR. Identification of Pirin as a Molecular Target of the CCG-1423/CCG-203971 Series of Antifibrotic and Antimetastatic Compounds. ACS Pharmacol Transl Sci. 2019 Apr 12;2(2):92-100

[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

 

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