CCG-1423 is a small-molecule inhibitor of RhoA transcriptional signaling. CCG-1423 potently (<1 mumol/L) inhibits lysophosphatidic acid-induced DNA synthesis in PC-3 prostate cancer cells, and whereas it inhibits the growth of RhoC-overexpressing melanoma lines (A375M2 and SK-Mel-147) at nanomolar concentrations, it is less active on related lines (A375 and SK-Mel-28) that express lower levels of Rho.
In H9c2 cells, CCG-1423 inhibits MRTF nuclear localization, and completely blocks STARS proximal reporter activity. In vivo, pharmacological SRF inhibition by CCG-1423 reduced nuclear MKL1 and improved glucose uptake and tolerance in insulin-resistant mice.
|Cell lines||Overexpress RhoC melanoma lines (A375M2 and SK-Mel-147), low RhoC-expressing lines (A375 and SK-Mel-28), transformed (SW962, PC-3 and SKOV-3) and nontransformed (WI-38) cell lines|
|Preparation method||Cells in normal culture medium are plated (2,000 per well) in a 96-well plate coated with laminin. After attachment, the medium is replaced with serum-free medium (0% FBS) with 30 μmol/L LPA with or without 300 nM CCG-1423. Fresh LPA with or without CCG-1423 is added at day 5 to ensure that LPA and compound are present throughout the experiment. On day 8, WST-1 reagent is added to the wells for 1 h and absorbance at 450 nm is read using a Victor plate reader.|
|Incubation time||72 hours|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO: ≥ 40 mg/mL|
Novel Rho/MRTF/SRF inhibitors block matrix-stiffness and TGF-β-induced fibrogenesis in human colonic myofibroblasts.
Johnson LA, et al. Inflamm Bowel Dis. 2014 Jan;20(1):154-65. PMID: 24280883.
STARS is essential to maintain cardiac development and function in vivo via a SRF pathway.
Chong NW, et al. PLoS One. 2012;7(7):e40966. PMID: 22815879.
Combination of small molecules enhances differentiation of mouse embryonic stem cells into intermediate mesoderm through BMP7-positive cells.
Mae S, et al. Biochem Biophys Res Commun. 2010 Mar 19;393(4):877-82. PMID: 20171952.
CCG-1423: a small-molecule inhibitor of RhoA transcriptional signaling.
Evelyn CR, et al. Mol Cancer Ther. 2007 Aug;6(8):2249-60. PMID: 17699722.
|Related Ras Products|
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MLS000532223 is a selective inhibitor of Rho family GTPases, with EC50 ranging from 16 μM to 120 μM.
BI-3406 is a highly potent and selective SOS1::KRAS inhibitor (IC50=6 nM), which selectively binds to SOS1 and blocks the interaction with KRAS, irrespective of the KRAS mutation.
ZT-12-037-01 is a potent, selective, ATP-competitive STK19 inhibitor with IC50 values of 23.96 nM and 27.94 nM for STK19 (WT) and STK19 (D89N), respectively.
BI-2852 is a potent KRAS inhibitor that binds with nanomolar affinity to a pocket.
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