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| Targets |
PF-06952229 targets the TGF-β receptor type I (TGFBR1), a serine/threonine kinase. TGF-β signaling plays a crucial role in tumor progression, metastasis, and immune evasion. By inhibiting TGFbR1, PF-06952229 prevents the phosphorylation of SMAD2 (pSMAD2) in both tumor and immune cells, thereby reducing TGF-β signaling. This inhibition reverses epithelial-to-mesenchymal transition (EMT) in vitro and modulates the tumor immune microenvironment.
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| ln Vitro |
PF-06952229 demonstrates potent in vitro activity as a TGFbR1 inhibitor, with an IC50 of 24 nM. At 0.5 μM, it achieves 94% inhibition of pSMAD2. The compound reverses EMT in vitro and modulates the tumor immune microenvironment. Its activity is assessed in cell-based assays measuring TGF-β-induced SMAD2 phosphorylation and downstream gene expression. PF-06952229's selectivity and potency make it a valuable tool for studying TGF-β signaling in cancer.
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| ln Vivo |
In the MCF7 ER+ xenograft breast cancer tumor model, PF-06952229 (oral gavage; 30 mg/kg; twice daily; 21 days) paired with palbociclib for 21 days increases pSMAD2 suppression. Comparing this combination to PF-06952229 monotherapy, survival was likewise markedly increased [1].
In vivo, PF-06952229 has demonstrated antitumor activity in mouse models. As an orally available compound, it can be administered conveniently. It modulates the tumor immune microenvironment, which is critical for its antineoplastic effects. PF-06952229 is being investigated for the treatment of solid tumors, particularly metastatic breast cancer. Its ability to inhibit TGF-β signaling and reverse EMT in vivo contributes to its potential as a therapeutic agent. |
| Enzyme Assay |
In vitro enzyme assays for PF-06952229 typically involve measuring its inhibition of TGFbR1 kinase activity. These assays use recombinant TGFbR1 (ALK5) and a peptide substrate in the presence of ATP. The phosphorylation of the substrate is measured to determine the IC50 (24 nM). Selectivity profiling against a panel of kinases is performed to confirm specificity. Additionally, cellular assays measuring pSMAD2 levels are used to confirm target engagement and functional inhibition.
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| Cell Assay |
In vitro cellular assays for PF-06952229 are conducted in cancer cell lines and immune cells. Cells are treated with the compound at varying concentrations, and TGF-β-induced SMAD2 phosphorylation is measured by Western blot or phospho-specific ELISA. EMT reversal is assessed by measuring epithelial (e.g., E-cadherin) and mesenchymal (e.g., vimentin) markers. Cell proliferation and migration assays are performed to evaluate the functional consequences of TGF-β inhibition.
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| Animal Protocol |
Animal/Disease Models: MCF-7 ER+ HER2-xenograft breast cancer tumor model [1]
Doses: 30 mg/kg Route of Administration: po (oral gavage); twice (two times) daily; 44 days Experimental Results: Tumor growth inhibition when combined with Palbociclib Enhance. In vivo animal experiments with PF-06952229 are conducted in mouse xenograft models of solid tumors. Tumor-bearing mice are administered PF-06952229 orally at various doses. Tumor growth is monitored, and tumor tissues are harvested for analysis of pSMAD2 levels, EMT markers, and immune cell infiltration. Pharmacodynamic studies are performed to confirm target engagement and modulation of the tumor microenvironment. |
| ADME/Pharmacokinetics |
PF-06952229 is an orally active compound with favorable pharmacokinetic properties. It has a molecular weight of approximately 424.9 g/mol. The compound is typically stored as a powder at -20°C (3 years) or 4°C (2 years), and in solution at -80°C (6 months) or -20°C (1 month). Its half-life, bioavailability, and tissue distribution have been characterized in preclinical studies to support its efficacy in mouse models.
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| Toxicity/Toxicokinetics |
Comprehensive toxicological data for PF-06952229 are primarily derived from preclinical studies. The compound is intended for research use only and is not approved for human therapeutic use. In animal models, PF-06952229 has been shown to be well-tolerated at efficacious doses. Standard safety assessments include monitoring of body weight, clinical signs, and organ histopathology in animal studies. Further toxicity studies would be required for clinical development.
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| References | |
| Additional Infomation |
PF-06952229, a TGF-β receptor 1 inhibitor, is an orally bioavailable transforming growth factor-β receptor 1 (TGFβR1) inhibitor with potential anti-tumor activity. After administration, PF-06952229 specifically targets and binds to TGFβR1, thereby blocking TGFβR1-mediated signal transduction. This eliminates TGFβR1-mediated immunosuppression, enhances anti-tumor immunity in the tumor microenvironment (TME), and promotes cytotoxic T lymphocyte (CTL)-mediated immune responses against tumor cells, ultimately leading to tumor cell death. This may reduce TGFβR1-dependent cancer cell proliferation. The TGFβ signaling pathway is frequently dysregulated in tumors and plays a crucial role in the regulation of cell growth, differentiation, apoptosis, migration, invasion, and angiogenesis. It plays a key role in immunosuppression within the tumor microenvironment.
PF-06952229 is a potent, selective, and orally active TGFbR1 (ALK5) inhibitor being developed as an antineoplastic agent. It has an IC50 of 24 nM and achieves 94% inhibition of pSMAD2 at 0.5 μM. The compound reverses EMT in vitro and modulates the tumor immune microenvironment. It is being investigated for the treatment of solid tumors, especially metastatic breast cancer. PF-06952229 is also known as MDV6058. |
| Molecular Formula |
C23H24CLFN4O3
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| Molecular Weight |
458.913067817688
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| Exact Mass |
458.152
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| CAS # |
1801333-55-0
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| PubChem CID |
118211239
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| Appearance |
White to off-white solid powder
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
32
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| Complexity |
598
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=CC=C(C(=C1)C1=CC(=C(C=N1)C(C)C)NC1C=CN=CC=1C(NC(CO)CO)=O)F
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| InChi Key |
IPBLCOKXDQHSQW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H24ClFN4O3/c1-13(2)17-10-27-21(16-7-14(24)3-4-19(16)25)8-22(17)29-20-5-6-26-9-18(20)23(32)28-15(11-30)12-31/h3-10,13,15,30-31H,11-12H2,1-2H3,(H,28,32)(H,26,27,29)
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| Chemical Name |
4-[[2-(5-chloro-2-fluorophenyl)-5-propan-2-ylpyridin-4-yl]amino]-N-(1,3-dihydroxypropan-2-yl)pyridine-3-carboxamide
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| Synonyms |
PF06952229 PF 06952229
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~108.95 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.45 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1791 mL | 10.8954 mL | 21.7908 mL | |
| 5 mM | 0.4358 mL | 2.1791 mL | 4.3582 mL | |
| 10 mM | 0.2179 mL | 1.0895 mL | 2.1791 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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