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| 10mg |
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| 25mg |
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| 100mg |
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Purity: ≥98%
AZD0364 is a potent and selective oral inhibitor of ERK1/2 that is efficacious in both monotherapy and combination therapy in models of NSCLC. For ERK2, it has an IC50 of 0.6 nM. As an example, AZD0364 inhibits the phosphorylation of p90RSK in BRAF mutant A375 cells with an IC50 value of 6 nM. It is also highly selective (10/329 kinases tested are inhibited at >50% at 1 µM). Over 50% of tumor cell lines that are sensitive to AZD0364 have genetic changes in the RAS/MAPK pathway, such as BRAF, NRAS, or KRAS mutations, according to an objective cell proliferation screen of 750 tumor cell lines. Combining AZD0364 and selumetinib (AZD6244, ARRY-142886) therapy is highly synergistic in a subset of NSCLC cell lines harboring KRAS mutations.
| Targets |
ERK2 (IC50 = 0.6 nM)
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|---|---|
| ln Vitro |
AZD0364 exhibits high cellular potency against a direct downstream substrate on the MAPK pathway (e.g., phospho-p90RSK1 inhibition in BRAFV600E mutant A375 cells, IC50 = 6 nM). According to SPR on human unphosphorylated-ERK2: pKd = 10; t1/2 = 277 mins[2], the molecule has a long residence time on the protein and is a highly selective kinase inhibitor (10/329 kinases tested are inhibited at >50% at a 1 µM)[2].
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| ln Vivo |
AZD0364 has good oral pharmacokinetics across species. AZD0364 inhibits phospho-p90RSK1 in tumors in xenograft models in a dose-dependent manner. In the KRAS mutant NSCLC Calu 6 xenograft model, AZD0364 causes regressions. In KRAS mutant NSCLC xenograft models, AZD0364 can also be used safely and successfully in combination with the MEK1/2 inhibitor selumetinib[2].
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| Enzyme Assay |
AZD-0364 is measured using the A375 phospho-p90RSK assay and ERK2 mass spectrometry, with IC50 values of 0.6 nM and 5.7 nM, respectively. As a monotherapy, AZD-0364 can slow the growth of a variety of cancer cell lines (including the A549, H2122, H2009, and Calu6 cell lines with KRAS mutations), and Selumetinib treatment can further enhance this effect.
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| Cell Assay |
KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) A549, H2122, H2009, and Calu6 cell lines are seeded in 384-well black, clear bottomed plates, cultured for 18-24 hours and treated with increasing concentrations of AZD-0364 (7.143 nM, 61 nM, 357 nM, 2.143 μM and 10 μM) and Selumetinib (0-10 μM) in a 6×6 dosing matrix. Cells are sown at a density such that at the end of the assay, cells in untreated wells are roughly 80% confluent. A Sytox Green endpoint is used to calculate the live cell number three days after treatment[1].
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| Animal Protocol |
Mice: A549 is a line of non-small cell lung cancer in humans that carries the G12S mutation in the KRAS gene, which causes cancer. 5×106 A549 cells (ATCC) from each female naked mouse are implanted subcutaneously (s.c.) on the left flank. Calculated volumes and twice-weekly calliper measurements are used to track tumor growth. Animals are divided into groups of 7–11 and treated with a continuous combination schedule of selumetinib (ARRY-142886), 25 mg/kg BiD, and AZD–0364, 25 mg/kg QD (four hours after the first selumetinib dose). Both medications are administered orally. Following the start of dosing, tumor volumes are measured twice weekly[1].
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| References | |
| Additional Infomation |
Tizaterkib is an orally bioavailable inhibitor of the extracellular signal-regulated kinases 1 (ERK1) and 2 (ERK2), with potential antineoplastic activity. Upon oral administration, tizaterkib specifically targets, binds to and inhibits the activity of the serine/threonine-protein kinases ERK1 and ERK2, thereby preventing the phosphorylation of ERK1/2 substrates and the activation of mitogen-activated protein kinase (MAPK)/ERK-mediated signal transduction pathways. This results in the inhibition of ERK-dependent proliferation and survival of tumor cells. The MAPK/ERK pathway, also known as the RAS/RAF/MEK/ERK pathway, is hyperactivated in a variety of tumor cell types due to mutations in upstream targets. It plays a key role in the proliferation, differentiation and survival of tumor cells.
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| Molecular Formula |
C24H24F2N8O2
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|---|---|---|
| Molecular Weight |
494.496570587158
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| Exact Mass |
494.2
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| Elemental Analysis |
C, 58.29; H, 4.89; F, 7.68; N, 22.66; O, 6.47
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| CAS # |
2097416-76-5
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| Related CAS # |
2097416-77-6 (ethanesulonate);2097416-76-5;2097416-93-6 (hemiadipate);
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| PubChem CID |
129116690
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| Appearance |
White to off-white solid powder
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| LogP |
2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
36
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| Complexity |
768
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=CN=C(N=C1C2=CN3C[C@@H](N(C(=O)C3=N2)CC4=CC(=C(C=C4)F)F)COC)NC5=CC=NN5C
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| InChi Key |
HVIGNZUDBVLTLU-MRXNPFEDSA-N
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| InChi Code |
InChI=1S/C24H24F2N8O2/c1-14-9-27-24(30-20-6-7-28-32(20)2)31-21(14)19-12-33-11-16(13-36-3)34(23(35)22(33)29-19)10-15-4-5-17(25)18(26)8-15/h4-9,12,16H,10-11,13H2,1-3H3,(H,27,30,31)/t16-/m1/s1
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| Chemical Name |
(6R)-7-[(3,4-difluorophenyl)methyl]-6-(methoxymethyl)-2-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5,6-dihydroimidazo[1,2-a]pyrazin-8-one
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.21 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 | 2.0222 mL | 10.1112 mL | 20.2224 mL | |
| 5 mM | 0.4044 mL | 2.0222 mL | 4.0445 mL | |
| 10 mM | 0.2022 mL | 1.0111 mL | 2.0222 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04305249 | Recruiting | Drug: ATG-017 Drug: ATG-017+Nivolumab |
Solid Tumor Hematological Malignancy |
Antengene Therapeutics Limited | August 15, 2020 | Phase 1 |
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