Physicochemical Properties
| Molecular Formula | C30H29F3N6O3 |
| Molecular Weight | 578.584876775742 |
| Exact Mass | 578.225 |
| CAS # | 2804039-78-7 |
| Related CAS # | GZD856;1257628-64-0 |
| PubChem CID | 155981976 |
| Appearance | Off-white to light yellow solid powder |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 10 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 42 |
| Complexity | 920 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | FC(C1C=C(C=CC=1CN1CCN(C)CC1)NC(C1C=CC(C)=C(C#CC2C=NC3=CC=NN3C=2)C=1)=O)(F)F.OC=O |
| InChi Key | CZBBDTJTQDJXAO-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C29H27F3N6O.CH2O2/c1-20-3-5-23(15-22(20)6-4-21-17-33-27-9-10-34-38(27)18-21)28(39)35-25-8-7-24(26(16-25)29(30,31)32)19-37-13-11-36(2)12-14-37;2-1-3/h3,5,7-10,15-18H,11-14,19H2,1-2H3,(H,35,39);1H,(H,2,3) |
| Chemical Name | formic acid;4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-(2-pyrazolo[1,5-a]pyrimidin-6-ylethynyl)benzamide |
| 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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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
| Targets | PDGFRα 68.6 nM (IC50) PDGFRβ 136.6 nM (IC50) Bcr-AblT315I 15.4 nM (IC50) Bcr-Abl 19.9 nM (IC50) |
| ln Vitro | GZD856 has antiproliferative efficacy against a panel of lung cancer cells at 0.0032-10 μM over 72 hours[1]. H1703 cells undergo a dose-dependent G0/G1 phase arrest and apoptosis when exposed to GZD856 (0.3-3 μM; 24-28 h) but not A549 cells[1]. In H1703 and A549 cells, GZD856 (0.1-10 μM; 6 h) dose-dependently suppresses downstream signaling and PDGFRα/β phosphorylation[1]. With IC50s of 2.2, 67.0, 0.64, and 10.8 nM, respectively, GZD856 suppresses the proliferation of K562, K562R (Q252H), and murine Ba/F3 cells ectopically expressing Bcr-AblWT and Bcr-AblT315I[2]. |
| ln Vivo | GZD856 (10-30 mg/kg, po once daily for 16 days) is well-tolerated and exhibits strong anticancer efficacy in the lung cancer models H1703 and A549. In an A549-Luc orthotopic model, GZD856 suppresses the spread of lung cancer cells to the brain and liver [1]. In mice containing xenograft K562 and Ba/F3 cells expressing Bcr-AblT315I, GZD856 (10 mg/kg; po once daily for 8 d) potently suppresses tumor growth[2]. A single intravenous dose of GZD856 (5 mg/kg) results in an extended half-life (T1/2=19.97 h), the best plasma exposure (Cmax=934.38 μg/L), and an AUC0-∞ (8165.8 μg/L·h) in rats[1]. Rats treated with a single oral dose of GZD856 (25 mg/kg) show optimal plasma exposure (Cmax = 899.5 μg/L), a long half-life (T1/2 = 22.2 h), and good oral bioavailability (BA = 78%)[1]. |
| Cell Assay |
Cell Viability Assay[1] Cell Types: H1703, A549, Calu-6, 95-D, L-78, HCC827, SPCA-1, H1650, H1299, H522, H332 and H820 NSCLC cells Tested Concentrations: 0.0032 -10 μM Incubation Duration: 72 hrs (hours) Experimental Results: Inhibited PDGFRα-overexpressing H1703 cells, with an IC50 of 0.25 μM. Apoptosis Analysis[1] Cell Types: H1703 and A549 NSCLC cells Tested Concentrations: 0.3, 1, 3 μM Incubation Duration: 24, 48 hrs (hours) Experimental Results: Led to 54.1% apoptosis in H1703 cells at the concentration of 3.0 µM, whereas only 15.5% apoptotic A549 cells were observed under similar conditions. diminished the CDK4, cyclin D2, CDK2 and Cyclin E protein levels and activated of PARP and Caspase-3 cleavage in H1703 cells. Western Blot Analysis[1] Cell Types: H1703 and A549 NSCLC cells Tested Concentrations: 0.1-10 μM Incubation Duration: 6 hrs (hours) Experimental Results: Inhibited the phosphorylation of PDGFRα and PDGFRβ in a dose-dependent manner. Observed the activation of downstream AKT, ERK1/2 and STAT3, with no obvious effects on total protein levels. |
| Animal Protocol |
Animal/Disease Models: Male CB17-SCID (severe combined immunodeficient) mouse implanted with H1703 and A549 cancer cells[1] Doses: 10, 30 mg/kg Route of Administration: po (oral gavage) one time/day for 16 days Experimental Results: Displayed antitumor effects in H1703-xenograft mice, with tumor growth inhibition (TGI) values of 20.8% and 74.1% at dosages of 10 and 30 mg/kg, respectively. Displayed antitumor effects in A549-xenograft mice, with a TGI value of 51.1% at 30 mg/kg. Was well tolerated in all of the tested groups, with no mortality or significant loss of body weight. Animal/Disease Models: SD (Sprague-Dawley) rats (180-220 g)[1] Doses: 5 mg/kg for iv; 25 mg/kg for po (pharmacokinetic/PK Analysis) Route of Administration: A single intravenous (iv)injection and oral administration Experimental Results: Iv: T1/2=19.97 h; Cmax=934.38 μg/L; AUC0-∞= 8165.8 μg/L·h. Po: T1/2=22.2 h; Cmax=899.5 μg/L; BA=78%. |
| References |
[1]. GZD856, a novel potent PDGFRα/β inhibitor, suppresses the growth and migration of lung cancer cells in vitro and in vivo. Cancer Lett. 2016 May 28;375(1):172-178. [2]. Synthesis and identification of GZD856 as an orally bioavailable Bcr-Abl T315I inhibitor overcoming acquired imatinib resistance. J Enzyme Inhib Med Chem. 2017 Dec;32(1):331-336. |
Solubility Data
| Solubility (In Vitro) | DMSO : 100 mg/mL (172.84 mM) |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7284 mL | 8.6418 mL | 17.2837 mL | |
| 5 mM | 0.3457 mL | 1.7284 mL | 3.4567 mL | |
| 10 mM | 0.1728 mL | 0.8642 mL | 1.7284 mL |