Home MAPK ERK inhibitor Temuterkib (LY3214996)

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Temuterkib (LY3214996) ERK inhibitor

Cat.No.S8534

Temuterkib (LY3214996) is a selective and novel ERK1/2 inhibitor with IC50 of 5 nM for both enzymes in biochemical assays, and it potently inhibits cellular phospho-RSK1 in BRAF and RAS mutant cancer cell lines.
Temuterkib (LY3214996) ERK inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 453.56

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Chemical Information, Storage & Stability

Molecular Weight 453.56 Formula

C22H27N7O2S

 Storage (From the date of receipt)
CAS No. 1951483-29-6 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles CC1(C2=C(C=C(S2)C3=NC(=NC=C3)NC4=CC=NN4C)C(=O)N1CCN5CCOCC5)C

Solubility

In vitro
Batch:

DMSO : 27.5 mg/mL ( (60.63 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 15 mg/mL

Water : Insoluble

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In vivo
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Mechanism of Action

Targets/IC50/Ki
ERK1 [1]
(Cell-free assay)
5 nM
ERK2 [1]
(Cell-free assay)
5 nM
In vitro

Temuterkib (LY3214996) possesses an optimal balance of potency (hERK1 IC50 5 nM, hERK2 IC50 5nM, pRSK IC50 0.43 µM) and solubility[2]. 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 this compound[1].
In vivo

In tumor xenograft models, Temuterkib (LY3214996) inhibits PD biomarker phospho-p90RSK1 in tumors and the PD effects are correlated with compound exposures and anti-tumor activities. It 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 this compound as a single agent 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. In addition, it has anti-tumor activity in a A375 melanoma xenograft model due to MAPK reactivation, may have potential for treatment of melanoma patients who have failed BRAF therapies. More importantly, it can be combined with investigational and approved agents in preclinical models, particularly KRAS mutant models. Combination treatment with a CDK4/6 inhibitor is 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[1].

This compound has good PK properties (dog, AUCoral 23800 nM*hr, CL 12.1 mL/min/kg, bioavailability 75.4%), IVTI (TED50 =16 mg/kg pRSK1) and demonstrates significant in vivo efficacy in several human cancer xenograft models[2].
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT04916236 Recruiting
Pancreatic Cancer|Colorectal Cancer|Non-small Cell Lung Cancer|KRAS Mutation-Related Tumors
The Netherlands Cancer Institute|Lustgarten Foundation
 March 31 2022 Phase 1
NCT04033341 Completed
Healthy
Eli Lilly and Company
 August 1 2019 Phase 1

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