JND-3229 is a novel reversible EGFRC797S Mutant (EGFRC797S) inhibitor with anticancer activity. It inhibits EGFR mutants with IC50 values of 5.8, 6.8 and 30.5 nM for EGFRL858R/T790M/C797S, EGFRWT and EGFRL858R/T790M, respectively.
Physicochemical Properties
| Molecular Formula | C33H41CLN8O2 |
| Molecular Weight | 617.184045553207 |
| Exact Mass | 616.304 |
| CAS # | 2260886-64-2 |
| PubChem CID | 137628688 |
| Appearance | White to light yellow solid powder |
| LogP | 5 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 7 |
| Heavy Atom Count | 44 |
| Complexity | 973 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | ClC1C=CC=CC=1N1CC2=CN=C(NC3C=CC(=C(C)C=3)N3CCN(C)CC3)N=C2N(C1=O)C1CCC(CC1)NC(CC)=O |
| InChi Key | WVLWGBZNXIVAKC-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C33H41ClN8O2/c1-4-30(43)36-24-9-12-26(13-10-24)42-31-23(21-41(33(42)44)29-8-6-5-7-27(29)34)20-35-32(38-31)37-25-11-14-28(22(2)19-25)40-17-15-39(3)16-18-40/h5-8,11,14,19-20,24,26H,4,9-10,12-13,15-18,21H2,1-3H3,(H,36,43)(H,35,37,38) |
| Chemical Name | N-[4-[3-(2-chlorophenyl)-7-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-1-yl]cyclohexyl]propanamide |
| 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 | With IC50 values of 0.51, 0.32, 0.31, and JND3229 (0.1, 0.3, 1, 3, 10 μM; 2 hours), it is effective in inhibiting the phosphorylation of EGFRL858R/T790M/C797S and EGFR >19D/T790M/C797S in engineered BaF3 batteries. It also effectively inhibits BaF3 cells (marked EGFRL858R/T790M/C797S and EGFR19D/T790M/C797S), NCI-H1975 NSCLC cells (EGFRT790M), and A431 vision (overexpressing EGFRWT). |
| ln Vivo | JND3229 (10 mg/kg; intraperitoneal injection; twice day for 10 tumor days) showed substantial growth suppression in vivo [1]. |
| Cell Assay |
Western Blot Analysis[1] Cell Types: BaF3 cells (overexpressing EGFRL858R/T790M/C797S or EGFR19D/T790M/C797S) Tested Concentrations: 0.1, 0.3, 1, 3, 10 µM Incubation Duration: 2 h Experimental Results: Dramatically inhibited EGFRL858R Phospho/T790M/C797S and EGFR19D/T790M/C797S in a dose-dependent manner. |
| Animal Protocol |
Animal/Disease Models: BALB/c mouse (bearing the establishment of BaF3-EGFR19D/T790M/C797S mouse xenograft tumor model) [1]. Doses: 10 mg/kg Route of Administration: intraperitoneal (ip) injection; twice (two times) daily for 10 days. Experimental Results: It had a significant inhibitory effect on tumor growth, and the tumor growth inhibition (TGI) value was 42.2%. Treatment animals were well tolerated, with no significant weight loss or other obvious signs of toxicity. Dramatically reduces the levels of phosphorylated EGFR (p-EGFR) in tumor tissues. |
| References |
[1]. Discovery of JND3229 as a New EGFRC797S Mutant Inhibitor with In Vivo Monodrug Efficacy. ACS Med Chem Lett. 2018 Oct 8;9(11):1123-1127. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~12.5 mg/mL (~20.25 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (2.03 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 12.5 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: ≥ 1.25 mg/mL (2.03 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 12.5 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: ≥ 1.25 mg/mL (2.03 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 12.5 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 | 1.6203 mL | 8.1014 mL | 16.2027 mL | |
| 5 mM | 0.3241 mL | 1.6203 mL | 3.2405 mL | |
| 10 mM | 0.1620 mL | 0.8101 mL | 1.6203 mL |