KO-947 is a novel, potent and selective ERK1/2 kinase inhibitor that may be helpful in treating tumors with dysregulated MAPK pathways. Slow dissociation kinetics are exhibited by KO-947. The tumor cells that exhibit dysregulation of the MAPK pathway, including mutations in the BRAF, NRAS, or KRAS, proliferated and were effectively inhibited by KO-947. In preclinical models that are resistant to BRAF and MEK inhibitors, KO-947 also reduces MAPK signaling and cellular proliferation. KO-947 causes tumor regressions in tumor models with BRAF or RAS mutations as well as tumor models without BRAF or RAS mutations but with other MAPK pathway dysregulations.
Physicochemical Properties
| Molecular Formula | C21H17N5O |
| Molecular Weight | 355.392583608627 |
| Exact Mass | 355.14 |
| Elemental Analysis | C, 70.97; H, 4.82; N, 19.71; O, 4.50 |
| CAS # | 1695533-89-1 |
| Related CAS # | 1695533-89-1 |
| PubChem CID | 136653617 |
| Appearance | White to off-white solid powder |
| LogP | 2.4 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 3 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 27 |
| Complexity | 531 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | ODIUJYZERXVGEI-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C21H17N5O/c27-21-23-18-11-19-17(20(25-24-19)15-6-8-22-9-7-15)10-16(18)13-26(21)12-14-4-2-1-3-5-14/h1-11H,12-13H2,(H,23,27)(H,24,25) |
| Chemical Name | 6-benzyl-3-pyridin-4-yl-5,8-dihydro-1H-pyrazolo[4,3-g]quinazolin-7-one |
| Synonyms | KO-947; KO947; KO 947 |
| 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: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 | ERK1; ERK2 |
| ln Vitro | KO-947 is an ERK inhibitor with at least 50-fold selectivity against a panel of 450 kinases that has a 10 nM concentration. In tumor cells with dysregulated MAPK pathway signaling, such as those with BRAF, NRAS, or KRAS mutations, KO-947 inhibits ERK signaling and proliferation at low nanomolar concentrations[1]. |
| ln Vivo | KO-947 induces regressions in RAS- and RAF-mutant melanoma, NSCLC, and pancreatic cancer models on administration schedules ranging from daily to weekly in cell-line derived xenograft studies and profoundly suppresses ERK signaling for up to five days after a single dose. Similar antitumor activity is made possible by intermittent dosing at a lower dose intensity[1]. |
| References |
[1]. KO-947, a potent ERK inhibitor with robust preclinical single agent activity in MAPK pathway dysregulated tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, D |
| Additional Infomation | ERK1/2 Inhibitor KO-947 is an inhibitor of the extracellular signal-regulated kinases (ERK) 1 and 2, with potential antineoplastic activity. Upon intravenous administration, KO-947 specifically binds to and inhibits both ERK 1 and 2, thereby preventing the activation of mitogen-activated protein kinase (MAPK)/ERK-mediated signal transduction pathways. This results in the inhibition of ERK-dependent tumor cell proliferation and survival. The MAPK/ERK pathway is often upregulated in a variety of tumor cell types and plays a key role in the proliferation, differentiation and survival of tumor cells. |
Solubility Data
| Solubility (In Vitro) | DMSO: 62.5~71 mg/mL (175.9~199.8 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.85 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 (5.85 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 (5.85 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 | 2.8138 mL | 14.0691 mL | 28.1381 mL | |
| 5 mM | 0.5628 mL | 2.8138 mL | 5.6276 mL | |
| 10 mM | 0.2814 mL | 1.4069 mL | 2.8138 mL |