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Mechanistic Study of a Novel Thienyl Napthalenesulfonate Molecule that Selectively Inhibits Melanoma Cells with Constitutively‐Active ERK1/2
Author(s) -
Martinez Ramon,
Huang Weiliang,
Centola Garrick,
Samadani Ramin,
Chen Lijia,
Scheenstra Jacob,
Fletcher Steven,
Kane Maureen,
Mackerell Alexander,
Shapiro Paul
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.687.8
Subject(s) - mapk/erk pathway , neuroblastoma ras viral oncogene homolog , microbiology and biotechnology , chemistry , kinase , signal transduction , melanoma , cancer cell , cell growth , downregulation and upregulation , protein kinase a , cancer research , biochemistry , biology , cancer , mutation , gene , genetics , kras
The uncontrolled proliferation of cancer cells is often a result of constitutive activation of the extracellular signal‐regulated kinase (ERK 1/2) signaling pathway. Current trends in the design of kinase inhibitors for the ERK1/2 pathway employ the use of ATP‐competitive scaffolds, targeting the catalytic core of the proteins. As an alternative, we used computer‐aided drug design (CADD) to identify a novel thienyl napthalenesulfonate compound that selectively inhibits ERK2 at a binding site used by F‐site containing substrates, such as members of the Fos family of proteins. This compound has been shown to selectively inhibit the growth of melanoma cells that have constitutively active ERK1/2 via mutations in upstream activators BRaf or NRas. Proteomic and transcriptomic analysis of drug‐treated lysates showed inhibition in the expression of important downstream F‐site containing substrates of ERK 1/2, such as c‐Fos, Fra‐1, and c‐Myc. In addition, increased expression of the protein Nrf2, which is a regulator of pathways generating reactive oxygen species (ROS), suggests that this compound may be involved with impeding cell growth in melanoma cells via upregulation of oxidative stress pathways. When treating cells with known inhibitors of ROS, such as α‐tocopherol or N‐acetyl cysteine, partial to complete cellular proliferation is restored, further supporting implication of oxidative stress in the compound function. In this work, we attempt to further characterize and validate the regulatory mechanisms and apoptotic effect this novel compound is having on cancer cells, and how it can serve as a promising alternate line of therapy to traditional ATP‐competitive kinase inhibitors. Support or Funding Information This work was supported in part by an NIGMS Initiative for Maximizing Student Development Grant (2‐R25‐GM55036) and by an NIGMS Institutional Training Grant (T32 GM066706). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .