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ACS Med Chem Lett. 2014 Oct 17;6(1):47-52. doi: 10.1021/ml500198b. eCollection 2015 Jan 8.

Quantification of a Pharmacodynamic ERK End Point in Melanoma Cell Lysates: Toward Personalized Precision Medicine.

Author information

1
Division of Medicinal Chemistry, College of Pharmacy, Department of Biomedical Engineering, and Department of Chemistry, The University of Texas , Austin, Texas 78712, United States.
2
Department of Immunology and Department of Dermatology, The University of Texas MD Anderson Cancer Center , Houston, Texas 77030, United States.
3
Division of Medicinal Chemistry, College of Pharmacy, Department of Biomedical Engineering, and Department of Chemistry, The University of Texas , Austin, Texas 78712, United States ; Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University , 61519 Minia, Egypt.
4
Division of Medicinal Chemistry, College of Pharmacy, Department of Biomedical Engineering, and Department of Chemistry, The University of Texas , Austin, Texas 78712, United States ; Division of Medicinal Chemistry, College of Pharmacy, Department of Biomedical Engineering, and Department of Chemistry, The University of Texas , Austin, Texas 78712, United States.

Abstract

Protein kinases are mutated or otherwise rendered constitutively active in numerous cancers where they are attractive therapeutic targets with well over a dozen kinase inhibitors now being used in therapy. While fluorescent sensors have capacity to measure changes in kinase activity, surprisingly they have not been utilized for biomarker studies. A first-generation peptide sensor for ERK based on the Sox fluorophore is described. This sensor called ERK-sensor-D1 possesses high activity toward ERK and more than 10-fold discrimination over other MAPKs. The sensor can rapidly quantify ERK activity in cell lysates and monitor ERK pathway engagement by BRAF and MEK inhibitors in cultured melanoma cell lines. The dynamic range of the sensor assay allows ERK activities that have potential for profound clinical consequences to be rapidly distinguished.

KEYWORDS:

ERK; biomarker; melanoma

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