ERK1 (IC50 = 5 nM); ERK2 (IC50 = 5 nM)

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].

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].

LY3214996 demonstrated an optimal balance of potency (hERK1 IC50 5 nM, hERK2 IC50 5nM, pRSK IC50 0.43 µM) and solubility.

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.

[1]. Abstract 4973: Discovery of LY3214996, a selective and novel ERK1/2 inhibitor with potent antitumor activities in cancer models with MAPK pathway alterations. Cancer Res (2017) 77 (13_Supplement): 4973. https://doi.org/10.1158/1538-7445.AM2017-4973.

Temuterkib is an orally available inhibitor of extracellular signal-regulated kinase (ERK) 1 and 2, with potential antineoplastic activity. Upon oral administration, temuterkib 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 tumor cell proliferation, differentiation and survival.

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The RAS/MAPK pathway is dysregulated in approximately 30% of human cancers, and the extracellular-signal-regulated kinases (ERK1 and ERK2) serves as key central nodes within this pathway. The feasibility and clinical impact of targeting the RAS/MAPK pathway has been demonstrated by the therapeutic success of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma. However, resistance develops frequently through reactivation of the pathway. Therefore, simultaneous targeting of multiple effectors such as RAF, MEK and ERK in this pathway, offers a potential for enhanced efficacy while delaying and overcoming resistance. LY3214996 is a highly selective inhibitor of ERK1 and ERK2, with IC50 of 5 nM for both enzymes in biochemical assays. It potently inhibits cellular phospho-RSK1 in BRAF and RAS mutant cancer cell lines. In an unbiased tumor cell panel sensitivity profiling for inhibition of cell proliferation, tumor cells with MAPK pathway alterations including BRAF, NRAS or KRAS mutation are generally sensitivity to LY3214996. In tumor xenograft models, LY3214996 inhibits PD biomarker phospho-p90RSK1 in tumors and the PD effects are correlated with compound exposures and anti-tumor activities. LY3214996 shows either similar or superior anti-tumor activity as compared to other published ERK inhibitors in BRAF or RAS mutant cell lines and xenograft models. Oral administration of single-agent LY3214996 significantly inhibits tumor growth in vivo and is well tolerated in BRAF or NRAS mutant melanoma, BRAF or KRAS mutant colorectal, lung and pancreatic cancer xenografts or PDX models. Therefore, LY3214996 can be tailored for treatment of cancers with MAPK pathway alteration. In addition, LY3214996 has anti-tumor activity in a vemurafenib-resistant A375 melanoma xenograft model due to MAPK reactivation, may have potential for treatment of melanoma patients who have failed BRAF therapies. More importantly, LY3214996 can be combined with investigational and approved agents in preclinical models, particularly KRAS mutant models. Combination treatment of LY3214996 and CDK4/6 inhibitor abemaciclib was well tolerated and results in potent tumor growth inhibition or regression in multiple in vivo cancer models, including KRAS mutant colorectal and non-small cell lung cancers. Here, we first report the preclinical characterization of LY3214996, a novel small molecule ERK1/2 inhibitor currently in Phase I clinical trials in patients with advanced and metastatic cancers (NCT02857270).[1]

C22H27N7O2S

453.56

453.19

C, 58.26; H, 6.00; N, 21.62; O, 7.05; S, 7.07

1951483-29-6

1951483-29-6;2365171-00-0 (mesylate);

121408882

White to yellow solid powder

1.4±0.1 g/cm3

711.5±70.0 °C at 760 mmHg

384.1±35.7 °C

0.0±2.3 mmHg at 25°C

1.723

1.36

117Ų

CC1(C2=C(C=C(S2)C3=NC(=NC=C3)NC4=CC=NN4C)C(=O)N1CCN5CCOCC5)C

JNPRPMBJODOFEC-UHFFFAOYSA-N

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)

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

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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.

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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.

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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.
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 corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)