CCT251545Orally bioavailable and potent WNT signaling inhibitor CAS# 1661839-45-7 |
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| Cas No. | 1661839-45-7 | SDF | Download SDF |
| PubChem ID | 77050682 | Appearance | Powder |
| Formula | C23H24ClN5O | M.Wt | 421.92 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 50 mg/mL (118.51 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 8-[3-chloro-5-[4-(1-methylpyrazol-4-yl)phenyl]pyridin-4-yl]-2,8-diazaspiro[4.5]decan-1-one | ||
| SMILES | CN1C=C(C=N1)C2=CC=C(C=C2)C3=CN=CC(=C3N4CCC5(CCNC5=O)CC4)Cl | ||
| Standard InChIKey | LBFYQISQYCGDDW-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C23H24ClN5O/c1-28-15-18(12-27-28)16-2-4-17(5-3-16)19-13-25-14-20(24)21(19)29-10-7-23(8-11-29)6-9-26-22(23)30/h2-5,12-15H,6-11H2,1H3,(H,26,30) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | CCT251545 is an orally bioavailable and potent inhibitor of WNT signaling with IC50 value of 5 nM.
IC50 value: 5 nM [2]
Target: WNT
in vitro: CCT251545 is a potent and selective chemical probe for the human Mediator complex-associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. CCT251545 also reduces phospho-STAT1SER727 levels in SW620 cells with IC50 of 9 nM. CCT251545 is a small-molecule inhibitor of the WNT pathway discovered through cell-based screening. CCT251545 displays potent cell-based activity. CCT251545 alters WNT pathway-regulated gene expression and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1. [1] CCT251545 demonstrates weak inhibition of tankyrase enzymes (TNKS1 IC50 > 10 μM, TNKS2 IC50 = 15.0 ± 0 μM). CCT251545 potently inhibits reporter-based readouts of basal WNT pathway activity in LS174T and SW480 cells in the absence of WNT ligand or other stimulants (IC50 = 0.023 ± 0.011 μM and 0.190 ± 0.030 μM, respectively) and demonstrated potent inhibition of WNT3a ligand-dependent reporter readout in PA-1 cells (IC50 = 0.007 μM).[2]
in vivo: CCT251545 as a potent and selective chemical probe suitable for cell-based exploration of the reported context-dependent roles of CDK8 and CDK19 and associated kinase module subunits in human disease and other biological settings. [1] References: | |||||
CCT251545 Dilution Calculator
CCT251545 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.3701 mL | 11.8506 mL | 23.7012 mL | 47.4024 mL | 59.2529 mL |
| 5 mM | 0.474 mL | 2.3701 mL | 4.7402 mL | 9.4805 mL | 11.8506 mL |
| 10 mM | 0.237 mL | 1.1851 mL | 2.3701 mL | 4.7402 mL | 5.9253 mL |
| 50 mM | 0.0474 mL | 0.237 mL | 0.474 mL | 0.948 mL | 1.1851 mL |
| 100 mM | 0.0237 mL | 0.1185 mL | 0.237 mL | 0.474 mL | 0.5925 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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CCT251545 is an orally bioavailable and potent inhibitor of WNT signaling with IC50 value of 5 nM [1].
The WNT signaling network controls cellular functions such as proliferation and differentiation, and is a major regulator of mammalian development. WNT signaling is frequently deregulated in malignancy, especially in colon cancer, and plays an important role in the generation and maintenance of cancer stem cells [1].
CCT251545 is an orally bioavailable and potent WNT signaling inhibitor discovered through high-throughput cell-based screening. CCT251545 is also a potent and selective chemical probe for the human Mediator complex-associated protein kinases CDK8 and CDK19. CCT251545 changed gene expression regulated by WNT pathway and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1 [2]. CCT251545 also inhibited GSK3α and -β with IC50 values of 0.462 and 0.690 μM. In APC mutant human colorectal cancer cell line (COLO205-F1756 clone 4), CCT251545 inhibited WNT pathway activity with IC50 value of 0.035 nM [1].
In both mouse and rat, CCT251545 exhibited moderate clearance with moderate to high oral bioavailability. In mice bearing COLO205-F1756 clone 4 tumor xenografts, CCT251545 (70 mg/kg po bid for 9 days) significantly inhibited WNT signaling and reduced tumor weights by 37.5% [1].
References:
[1]. Mallinger A, Crumpler S, Pichowicz M, et al. Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen. J Med Chem, 2015, 58(4): 1717-1735.
[2]. Dale T, Clarke PA, Esdar C, et al. A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nat Chem Biol, 2015, 11(12): 973-980.
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Multilayered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/betacatenin signaling activation (Review).[Pubmed:29786110]
Int J Mol Med. 2018 Aug;42(2):713-725.
betacatenin/CTNNB1 is an intracellular scaffold protein that interacts with adhesion molecules (Ecadherin/CDH1, Ncadherin/CDH2, VEcadherin/CDH5 and alphacatenins), transmembranetype mucins (MUC1/CD227 and MUC16/CA125), signaling regulators (APC, AXIN1, AXIN2 and NHERF1/EBP50) and epigenetic or transcriptional regulators (BCL9, BCL9L, CREBBP/CBP, EP300/p300, FOXM1, MED12, SMARCA4/BRG1 and TCF/LEF). Gainoffunction CTTNB1 mutations are detected in bladder cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer and uterine cancer, whereas lossoffunction CTNNB1 mutations are also detected in human cancer. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA and ZNRF3 are representative betacatenin target genes. betacatenin signaling is involved in myofibroblast activation and subsequent pulmonary fibrosis, in addition to other types of fibrosis. betacatenin and NFkappaB signaling activation are involved in field cancerization in the stomach associated with Helicobacter pylori (H. pylori) infection and in the liver associated with hepatitis C virus (HCV) infection and other etiologies. betacatenintargeted therapeutics are functionally classified into betacatenin inhibitors targeting upstream regulators (AZ1366, ETC159, G007LK, GNF6231, ipafricept, NVPTNKS656, rosmantuzumab, vantictumab, WNTC59, WNT974 and XAV939), betacatenin inhibitors targeting proteinprotein interactions (CGP049090, CWP232228, E7386, ICG001, LF3 and PRI724), betacatenin inhibitors targeting epigenetic regulators (PKF118310), betacatenin inhibitors targeting mediator complexes (CCT251545 and cortistatin A) and betacatenin inhibitors targeting transmembranetype transcriptional outputs, including CD44v6, FZD7 and LGR5. Eradicating H. pylori and HCV is the optimal approach for the firstline prevention of gastric cancer and hepatocellular carcinoma (HCC), respectively. However, betacatenin inhibitors may be applicable for the prevention of organ fibrosis, secondline HCC prevention and treating betacatenindriven cancer. The multilayered prevention and treatment strategy of betacateninrelated human diseases is necessary for the practice of personalized medicine and implementation of precision medicine.
A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease.[Pubmed:26502155]
Nat Chem Biol. 2015 Dec;11(12):973-980.
There is unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545, a small-molecule inhibitor of the WNT pathway discovered through cell-based screening, is a potent and selective chemical probe for the human Mediator complex-associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates a type 1 binding mode involving insertion of the CDK8 C terminus into the ligand binding site. In contrast to type II inhibitors of CDK8 and CDK19, CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogs alter WNT pathway-regulated gene expression and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1. Consistent with this, we find that phosphorylation of STAT1(SER727) is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally, we demonstrate in vivo activity of CCT251545 in WNT-dependent tumors.
Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen.[Pubmed:25680029]
J Med Chem. 2015 Feb 26;58(4):1717-35.
WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.
