PF-06726304 is a novel, potent and selective SAM-competitive EZH2 (enhancer of zeste homolog 2) inhibitor with a Ki of 0.7 nM. PF-06726304 displayed improved LipE and on-target potency in both biochemical and cellular readouts relative to compound 18. PF-06726304 also displayed robust in vivo antitumor growth activity and dose-dependent de-repression of EZH2 target genes.
Physicochemical Properties
| Molecular Formula | C22H21CL2N3O3 |
| Molecular Weight | 446.326443433762 |
| Exact Mass | 445.095 |
| CAS # | 1616287-82-1 |
| Related CAS # | PF-06726304 acetate;2080306-28-9 |
| PubChem CID | 86723730 |
| Appearance | White to off-white solid powder |
| LogP | 3.6 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 30 |
| Complexity | 799 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | C1(=O)C2=C(C(Cl)=CC(C3=C(C)ON=C3C)=C2Cl)CCN1CC1=C(C)C=C(C)NC1=O |
| InChi Key | PDKDOPJQPKXNCT-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C22H21Cl2N3O3/c1-10-7-11(2)25-21(28)16(10)9-27-6-5-14-17(23)8-15(20(24)19(14)22(27)29)18-12(3)26-30-13(18)4/h7-8H,5-6,9H2,1-4H3,(H,25,28) |
| Chemical Name | 5,8-Dichloro-2-[(1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-7-(3,5-dimethyl-4-isoxazolyl)-3,4-dihydro-1(2H)-isoquinolinone |
| Synonyms | PF-6726304; PF 6726304; PF6726304; PF-06726304; PF 06726304; PF06726304; |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| ln Vitro | PF-06726304 (Compound 31) inhibits Karpas-422 H3K27me3 with an IC50 of 15 nM [1]. PF-06726304, with an IC50 of 25 nM, suppresses the growth of Karpas-422 cells carrying wild-type EZH2[1]. |
| ln Vivo | In a subcutaneous Karpas-422 xenograft model, PF-06726304 (200 and 300 mg/kg; BID 20 days) suppresses tumor development and causes a strong modification of downstream indicators [1]. |
| Animal Protocol |
Animal/Disease Models: Female Scid beige mice (6-8 weeks old) using Karpas-422 xenograft model [1] Doses: 200 and 300 mg/kg Route of Administration: BID for 20 days Experimental Results: Inhibited tumor growth and induced downstream organisms Robust modulation of markers in a subcutaneousKarpas-422 xenograft model. |
| References |
[1]. Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors. J Med Chem. 2016 Sep 22;59(18):8306-25. |
Solubility Data
| Solubility (In Vitro) | DMSO : ≥ 15 mg/mL (~33.61 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (2.24 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 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: ≥ 1 mg/mL (2.24 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 10.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 1 mg/mL (2.24 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 10.0 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 | 2.2405 mL | 11.2025 mL | 22.4049 mL | |
| 5 mM | 0.4481 mL | 2.2405 mL | 4.4810 mL | |
| 10 mM | 0.2240 mL | 1.1202 mL | 2.2405 mL |