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Purity: ≥98%
Temuterkib (formerly LY3214996; LY-3214996) is a selective, ATP-competitive, and orally bioavailable inhibitor with potential anticancer activity. In biochemical assays, it inhibits ERK1/2 with an IC50 value of 5 nM. In vitro and in vivo tests using BRAF-mutant models with acquired resistance showed that LY3214996 has antitumor activity. LY3214996 has progressed to an ongoing phase I clinical trial (NCT02857270) based on these preclinical data. The ERK pathway is crucial for oncogenesis, and about 30% of all human cancers have abnormalities in one or more of its components. The pathway's final node, ERK1/2 (ERK), controls cell survival, differentiation, and proliferation.
| Targets |
ERK1 (IC50 = 5 nM); ERK2 (IC50 = 5 nM)
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| ln Vitro |
Temuterkib has an IC50 of 5 nM for both ERK1 and ERK2 in biochemical assays, making it a highly selective inhibitor of these two enzymes. Temuterkib effectively inhibits cellular phospho-RSK1 in cancer cell lines containing the BRAF and RAS mutations. Tumor cells with MAPK pathway alterations, such as BRAF, NRAS, or KRAS mutations, are typically sensitive to Temuterkib in an unbiased tumor cell panel sensitivity profiling for inhibition of cell proliferation[1].
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| ln Vivo |
Temuterkib inhibits the phospho-p90RSK1 PD biomarker in tumors in tumor xenograft models, and the PD effects are correlated with compound exposures and anti-tumor activities. Comparing Temuterkib to other ERK inhibitors that have been published, it exhibits either comparable or superior anti-tumor activity in BRAF or RAS mutant cell lines and xenograft models. In BRAF or NRAS mutant melanoma, BRAF or KRAS mutant colorectal, lung, and pancreatic cancer xenografts or PDX models, oral administration of single-agent Temuterkib significantly inhibits tumor growth in vivo and is well tolerated. Temuterkib can therefore be modified for the treatment of cancers with altered MAPK pathways. Temuterkib also exhibits anti-tumor activity in a PLX4032-resistant A375 melanoma xenograft model, suggesting that it may be useful in treating melanoma patients who have received ineffective BRAF therapies. More significantly, Temuterkib can be used in preclinical models, particularly KRAS mutant models, in combination with investigational and approved agents. Temuterkib and the CDK4/6 inhibitor abemaciclib, when used in combination, are well tolerated and effectively inhibit tumor growth or cause it to shrink in a variety of in vivo cancer models, including KRAS mutant colorectal and non-small cell lung cancers[1].
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| Enzyme Assay |
LY3214996 demonstrated an optimal balance of potency (hERK1 IC50 5 nM, hERK2 IC50 5nM, pRSK IC50 0.43 µM) and solubility.
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| Cell Assay |
Tumor cells with MAPK pathway alterations, including BRAF, NRAS, or KRAS mutations, are generally sensitive to LY3214996 in an unbiased tumor cell panel sensitivity profiling for inhibition of cell proliferation.
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| References |
| Molecular Formula |
C22H27N7O2S
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| Molecular Weight |
453.56
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| Exact Mass |
453.19
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| Elemental Analysis |
C, 58.26; H, 6.00; N, 21.62; O, 7.05; S, 7.07
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| CAS # |
1951483-29-6
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| Related CAS # |
1951483-29-6;2365171-00-0 (mesylate);
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| Appearance |
Solid powder
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| SMILES |
CC1(C2=C(C=C(S2)C3=NC(=NC=C3)NC4=CC=NN4C)C(=O)N1CCN5CCOCC5)C
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| InChi Key |
JNPRPMBJODOFEC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H27N7O2S/c1-22(2)19-15(20(30)29(22)9-8-28-10-12-31-13-11-28)14-17(32-19)16-4-6-23-21(25-16)26-18-5-7-24-27(18)3/h4-7,14H,8-13H2,1-3H3,(H,23,25,26)
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| Chemical Name |
6,6-dimethyl-2-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-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 mg/mL (4.41 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 20.0 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 mg/mL (4.41 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 20.0 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. View More
Solubility in Formulation 3: ≥ 2 mg/mL (4.41 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2048 mL | 11.0239 mL | 22.0478 mL | |
| 5 mM | 0.4410 mL | 2.2048 mL | 4.4096 mL | |
| 10 mM | 0.2205 mL | 1.1024 mL | 2.2048 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 |
| NCT04005690 | Recruiting | Drug: Temuterkib Drug: Olaparib |
Stage II Pancreatic Cancer AJCC v8 Stage III Pancreatic Cancer AJCC v8 |
OHSU Knight Cancer Institute | August 1, 2019 | Early Phase 1 |
Ago1 promotes cell proliferation and migration though ERK1/2 not P38. aLevel of AGO1 protein was detected by western blotting assays.bLY3214996(ERK1/2) inhibitor significantly inhibited AGO1 cell growth compared to the normal group, while SB203580 (P38) did not significantly affect growth (*P Cell Death Dis.2018 Feb 27;9(3):324. |
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