CCT251545

Name: CCT251545
Brand: BOC Sciences
Rating: 5 (1 reviews)

CAS No.: 1661839-45-7

Cat No.: BP-300164 4.5

CCT251545 is a CDK8 and CDK19-associated WNT pathway inhibitor that can serve as a recognition scaffold for degradation-oriented studies of transcriptional kinase complexes. The ligand engages kinase targets involved in mediator complex signaling and WNT-regulated transcription, making it relevant to PROTAC strategies aimed at transcriptional pathway modulation. In a bifunctional degrader, the CCT251545-derived moiety would bind the CDK8 or CDK19 target, while a linker connects it to an E3 ligase recruiter to promote induced proximity with ubiquitination machinery. The intended mechanism is kinase ubiquitination and proteasome-dependent depletion, enabling comparison of pathway inhibition with protein-level removal. CCT251545 is useful for CDK8/CDK19 degrader exploration, WNT signaling research, mediator kinase biology, linker optimization, and analysis of degradation selectivity among transcription-associated kinases.

Structure of 1661839-45-7

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Ligand for Target Protein

Molecular Formula

C23H24ClN5O

Molecular Weight

421.92

Appearance

Solid powder

* For research and manufacturing use only. Not for human or clinical use.

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Capabilities & Facilities

Comprehensive PROTAC Platform
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Popular Publications Citing BOC Sciences Products

Solubility

DMSO: ≥ 50 mg/mL

Appearance

Solid powder

ShelfLife

2 years

Storage

Store in a cool and dry place and at 0 - 4°C for short term (days to weeks) or -64°C for long term (months to years).

Synonyms

8-[3-chloro-5-[4-(1-methylpyrazol-4-yl)phenyl]pyridin-4-yl]-2,8-diazaspiro[4.5]decan-1-oneCCT251545; CCT 251545; CCT-251545; CHEMBL34082138-(3-chloro-5-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyridin-4-yl)-2,8-diazaspiro[4.5]decan-1-one8-{3-Chloro-5-[4-(1-Methyl-1h-Pyrazol-4-Yl)ph

Boiling Point

709.7±60.0 °C | Condition: Press: 760 Torr

Density

1.37±0.1 g/cm3

InChI Key

LBFYQISQYCGDDW-UHFFFAOYSA-N

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)

SMILES

CN1C=C(C=N1)C2=CC=C(C=C2)C3=CN=CC(=C3N4CCC5(CCNC5=O)CC4)Cl

Mechanism

Mechanism of Action: CCT251545 supports customers investigating transcription-associated control of protein abundance. By inhibiting CDK8 and CDK19, it can help assess how mediator kinase signaling affects downstream pathway proteins, phosphorylation-dependent stability, and degradation-relevant transcriptional programs, including WNT- and STAT-linked networks.

Applications

• PROTAC-Mediated Degradation: CCT251545 can be used as a ligand component in PROTAC constructs to drive selective ubiquitin-proteasome–dependent degradation of its intended protein target. In PROTAC design, pairing this ligand with an E3 ligase-recruiting moiety enables systematic evaluation of ternary complex formation, ubiquitination efficiency, and degradation potency across relevant cell models.

• E3 Ligase Recruitment Optimization: Incorporate CCT251545 into PROTACs with alternative E3 ligase ligands to map how ligase choice affects target engagement and degradation kinetics. This direction supports rational screening of linker length and composition, aiming to maximize productive ternary complex stability while minimizing off-target degradation and non-specific proteolysis.

• Mechanistic Ternary Complex Studies: Use CCT251545-based PROTACs to probe the molecular determinants of ternary complex formation between the target protein and the recruited E3 ligase. Quantitative assays such as binding competition, degradation time-course profiling, and ubiquitination readouts help distinguish cooperative versus non-cooperative recruitment mechanisms.

• Structure–Activity Relationship Mapping: Build a series of CCT251545-containing PROTACs to conduct structure–activity relationship (SAR) studies focused on ligand geometry, attachment position, and linker architecture. By correlating these design variables with degradation magnitude, selectivity, and dose-response behavior, researchers can refine PROTACs toward improved efficacy and mechanistic clarity.

1. A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease

Paul A Clarke, Christina Esdar, Julian Blagg, Mark Stubbs, Rahul S Samant, Felix Rohdich, Gary Box, Maria-Jesus Ortiz-Ruiz, Klaus Schneider, Robert TePoele, Ken Ewan, Florence Raynaud, Paul Workman, Alexis de Haven Brandon, Suzanne A Eccles, Aurélie Mallinger, Sharon Gowan, Elizabeth Fraser, Daniel Schwarz, Melanie Valenti, Olajumoke Adeniji-Popoola, Andree Blaukat, Paul Czodrowski, Dirk Wienke, Will Court, Oliver Poeschke, Dennis Waalboer, Trevor Dale, Djordje Musil, Kai Schiemann, Richard Schneider Nat Chem Biol . 2015 Dec;11(12):973-980. doi: 10.1038/nchembio.1952.

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.

2. Multi‑layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β‑catenin signaling activation (Review)

Masaru Katoh Int J Mol Med . 2018 Aug;42(2):713-725. doi: 10.3892/ijmm.2018.3689.

β‑catenin/CTNNB1 is an intracellular scaffold protein that interacts with adhesion molecules (E‑cadherin/CDH1, N‑cadherin/CDH2, VE‑cadherin/CDH5 and α‑catenins), transmembrane‑type 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). Gain‑of‑function CTTNB1 mutations are detected in bladder cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer and uterine cancer, whereas loss‑of‑function 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 β‑catenin target genes. β‑catenin signaling is involved in myofibroblast activation and subsequent pulmonary fibrosis, in addition to other types of fibrosis. β‑catenin and NF‑κB 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. β‑catenin‑targeted therapeutics are functionally classified into β‑catenin inhibitors targeting upstream regulators (AZ1366, ETC‑159, G007‑LK, GNF6231, ipafricept, NVP‑TNKS656, rosmantuzumab, vantictumab, WNT‑C59, WNT974 and XAV939), β‑catenin inhibitors targeting protein‑protein interactions (CGP049090, CWP232228, E7386, ICG‑001, LF3 and PRI‑724), β‑catenin inhibitors targeting epigenetic regulators (PKF118‑310), β‑catenin inhibitors targeting mediator complexes (CCT251545 and cortistatin A) and β‑catenin inhibitors targeting transmembrane‑type transcriptional outputs, including CD44v6, FZD7 and LGR5. Eradicating H. pylori and HCV is the optimal approach for the first‑line prevention of gastric cancer and hepatocellular carcinoma (HCC), respectively. However, β‑catenin inhibitors may be applicable for the prevention of organ fibrosis, second‑line HCC prevention and treating β‑catenin‑driven cancer. The multi‑layered prevention and treatment strategy of β‑catenin‑related human diseases is necessary for the practice of personalized medicine and implementation of precision medicine.

3. Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen

Elizabeth Smith, Paul A Clarke, Christina Esdar, Julian Blagg, Mark Stubbs, Felix Rohdich, Gary Box, Maria-Jesus Ortiz-Ruiz, Ching Thai, Robert TePoele, Florence Raynaud, Frank Stieber, Paul Workman, Mark Pichowicz, Suzanne A Eccles, Alan T Henley, Katrin Georgi, Wynne Aherne, Aurélie Mallinger, Alexis De Haven Brandon, Birgitta Leuthner, Melanie Valenti, Olajumoke Adeniji-Popoola, William Court, Bozena Wood, Simon Crumpler, Dirk Wienke, Oliver Poeschke, Dennis Waalboer, Trevor Dale, Steve Hobbs, Kai Schiemann J Med Chem . 2015 Feb 26;58(4):1717-35. doi: 10.1021/jm501436m.

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.

ConcentrationVolumeMass	1 mg	5 mg	10 mg
0.1 mM	23.7 mL	118.51 mL	237.01 mL
0.5 mM	4.74 mL	23.7 mL	47.4 mL
1 mM	2.37 mL	11.85 mL	23.7 mL
5 mM	0.47 mL	2.37 mL	4.74 mL

CCT251545 is a Wnt-pathway-associated ligand scaffold suitable for exploratory degrader design after target validation. Its spirocyclic and heteroaryl features require careful linker-vector selection.

Structure: CCT251545 is a Wnt-pathway-associated ligand scaffold containing a chloropyridyl aryl system, N-methylpyrazole substituent, and a spirocyclic lactam-piperidine framework. The structure includes heteroaryl nitrogens, a lactam carbonyl, and a conformationally constrained spirocyclic amine.

Reactivity: CCT251545-derived PROTAC design should be treated as exploratory unless the relevant binding protein and tolerated exit vector are validated. Linker installation is most plausibly explored from the piperidine/spirocyclic periphery or heteroaryl substituent vectors in designed analogs. Alkyl, PEG, amide, carbamate, or tertiary-amine-compatible linkers may be paired with CRBN, VHL, or IAP ligands while preserving the chloropyridyl-pyrazole recognition region.

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* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂