DMX-5804 is a novel, potent, orally bioactive and selective MAP4K4 (Mitogen-activated protein kinase kinase kinase kinase-4) inhibitor with an IC50 of 3 nM, a pIC50 of 8.55 for human MAP4K4, less potent on MINK1/MAP4K6 (pIC50, 8.18), and TNIK/MAP4K7 (pIC50, 7.96). In mice, DMX-5804 reduces ischemia-reperfusion injury and improves cardiomyocyte survival. Human failing hearts and pertinent rodent models both activate the protein kinase kinase kinase kinase MAP4K4 (MAP4K4). We show that MAP4K4 is necessary for oxidative stress-induced death using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and gene silencing.
Physicochemical Properties
| Molecular Formula | C21H19N3O3 |
| Molecular Weight | 361.393864870071 |
| Exact Mass | 361.14 |
| Elemental Analysis | C, 69.79; H, 5.30; N, 11.63; O, 13.28 |
| CAS # | 2306178-56-1 |
| Related CAS # | 2306178-56-1 |
| PubChem CID | 137334091 |
| Appearance | Off-white to yellow solid powder |
| LogP | 2.9 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 27 |
| Complexity | 527 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | FUSHFOGORKZNNQ-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C21H19N3O3/c1-26-11-12-27-17-9-7-15(8-10-17)18-13-24(16-5-3-2-4-6-16)20-19(18)21(25)23-14-22-20/h2-10,13-14H,11-12H2,1H3,(H,22,23,25) |
| Chemical Name | 5-[4-(2-methoxyethoxy)phenyl]-7-phenyl-3H-pyrrolo[2,3-d]pyrimidin-4-one |
| Synonyms | DMX-5804; DMX 5804; DMX5804 |
| 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
| Targets | MAP4K4 (IC50 = 3 nM); MAP4K4 (pIC50 = 8.55); MINK1/MAP4K6 (pIC50 = 8.18); TNIK/MAP4K7 (pIC50 = 7.96); GCK/MAP4K2 (pIC50 = 6.50); KHS/MAP4K5 (pIC50 = 6.36); GLK/MAP4K3 (pIC50 = 4.95 nM); MLK1/MAP3K9 (pIC50 = 7.19); MLK3/MAP3K11 (pIC50 = 6.99); NUAK (pIC50 = 6.88); VEGFR (pIC50 = 5.72); ABL1 (pIC50 = 5.80 nM); Aurora B (pIC50 = 5.49 nM); FLT3 (pIC50 = 5.31); GSK3β (pIC50 = 4.66) |
| ln Vitro | DMX-5804 exhibits great selectivity at MAP4K4 over other kinases, such as GCK/MAP4K2 (pIC50, 6.50), GLK/MAP4K3 (pIC50, 4.95), GSK3β (pIC50, 4.66), KHS/MAP4K5 (pIC50, 6.36), MLK1/MAP3K9 (pIC50, 7.19), MLK3/MAP3K11 (pIC50, 6.99), NUAK (pIC50, 6.88) and VEGFR (pIC50, 5.72), ABL1 (pIC50, 5.80), Aurora B (pIC50, 5.49), FLT3 (pIC50, 5.31)[1]. |
| References |
[1]. MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo. Cell Stem Cell. 2019 Mar 1. pii: S1934-5909(19)30013-X. |
Solubility Data
| Solubility (In Vitro) |
DMSO: 72~125 mg/mL (199.2~345.9 mM) Ethanol: ~1.5 mg/mL (~4.2 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.76 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 20.8 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 (5.76 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 20.8 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: ≥ 2.08 mg/mL (5.76 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 | 2.7671 mL | 13.8355 mL | 27.6709 mL | |
| 5 mM | 0.5534 mL | 2.7671 mL | 5.5342 mL | |
| 10 mM | 0.2767 mL | 1.3835 mL | 2.7671 mL |