ZT-12-037-01 is a novel, potent, ATP-competitive and specific STK19-targeted inhibitor with IC50s of 23.96 nM and 27.94 nM for STK19 (WT) and STK19 (D89N), respectively. In vitro and in vivo, it is able to efficiently inhibit melanoma growth and oncogenic NRAS-driven melanocyte malignant transformation. It blocks the oncogenic NRAS-driven malignant transformation of melanocytes and interacts with STK19 protein with high affinity. An ATP-competitive inhibitor with an IC50 of 24 nM, ZT-12-037-01 prevents the phosphorylation of NRAS, the main isoform of the Ras family. Of all melanoma cases, 20% to 30% have activating mutations in NRAS. However, unlike BRAF, no anti-NRAS therapy has proven to be effective in decades of research.
Physicochemical Properties
| Molecular Formula | C21H31N5O2 |
| Molecular Weight | 385.50314450264 |
| Exact Mass | 385.25 |
| Elemental Analysis | C, 65.43; H, 8.11; N, 18.17; O, 8.30 |
| CAS # | 2328073-61-4 |
| PubChem CID | 138911316 |
| Appearance | White to off-white solid powder |
| LogP | 4.1 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 7 |
| Heavy Atom Count | 28 |
| Complexity | 495 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | AMAQJTHMSLYMFT-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C21H31N5O2/c1-13(2)26-9-7-15(8-10-26)22-20-16-11-18(27-3)19(28-4)12-17(16)24-21(25-20)23-14-5-6-14/h11-15H,5-10H2,1-4H3,(H2,22,23,24,25) |
| Chemical Name | 2-N-cyclopropyl-6,7-dimethoxy-4-N-(1-propan-2-ylpiperidin-4-yl)quinazoline-2,4-diamine |
| Synonyms | ZT-12-037-01; ZT-12-03701; ZT-12-037 01; ZT-12037-01; ZT-1203701; ZT-12037 01; ZT-1203701; ZT-1203701; ZT-1203701 |
| 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 | STK19 ( IC50 = 23.96 nM ); STK19 (D89N) ( IC50 = 27.94 nM ) |
| ln Vitro | ZT-12-037-01 treatment effectively inhibits NRAS phosphorylation in a time- and dose-dependent manner. Moreover, ZT-12-037-01'sIC50against STK19 increased in response to rising ATP concentrations, suggesting that ZT-12-037-01 is an ATP-competitive inhibitor of STK19. Mutant NRAS-STK19-driven melanocyte colony formation, proliferation, and tumor formation are all markedly inhibited by ZT-12-037-01 treatment. ZT-12-037-01'spro-apoptoticeffect is markedly amplified in cells that express oncogenic NRAS [1]. |
| ln Vivo | ZT-12-037-01 is a very effective STK19 inhibitor with low in vivo toxicity. Additionally, it treats SK-MEL-2 xenograft melanoma in a dose-dependent manner (with NRASQ61R)[1]. |
| Cell Assay |
Cell Line: CDK4 (R24C) melanocyte cells; hTERT melanocyte cells; p53DD melanocyte cells Concentration: 3 μM Incubation Time: 14 days Result: Inhibited melanocyte proliferation. |
| Animal Protocol |
SK-MEL-2 xenograft melanoma nude mice with hTERT/p53DD/CDK4(R24C) melanocytes 25 mg/kg; 50 mg/kg Intraperitoneally injection; 21 days; once a day |
| References |
[1]. Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis. Cell. 2019 Feb 21;176(5):1113-1127.e16. |
Solubility Data
| Solubility (In Vitro) |
1M HCl : 100 mg/mL (~259.40 mM) DMSO : ~50 mg/mL (~129.70 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: 5 mg/mL (12.97 mM) in 50% PEG300 +50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5940 mL | 12.9702 mL | 25.9403 mL | |
| 5 mM | 0.5188 mL | 2.5940 mL | 5.1881 mL | |
| 10 mM | 0.2594 mL | 1.2970 mL | 2.5940 mL |