Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics.

Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics.

Publication date: Aug 17, 2020

Whereas recent clinical studies report metastatic melanoma survival rates high as 30-50%, many tumors remain nonresponsive or become resistant to current therapeutic strategies. Analyses of The Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) data set suggests that a significant fraction of melanomas potentially harbor gain-of-function mutations in the gene that encodes for the ErbB4 receptor tyrosine kinase. In this work, a drug discovery strategy was developed that is based on the observation that the Q43L mutant of the naturally occurring ErbB4 agonist Neuregulin-2beta (NRG2?) functions as a partial agonist at ErbB4. NRG2?/Q43L stimulates tyrosine phosphorylation, fails to stimulate ErbB4-dependent cell proliferation, and inhibits agonist-induced ErbB4-dependent cell proliferation. Compounds that exhibit these characteristics likely function as ErbB4 partial agonists, and as such hold promise as therapies for ErbB4-dependent melanomas. Consequently, three highly sensitive and reproducible (Z’ > 0.5) screening assays were developed and deployed for the identification of small-molecule ErbB4 partial agonists. Six compounds were identified that stimulate ErbB4 phosphorylation, fail to stimulate ErbB4-dependent cell proliferation, and appear to selectively inhibit ErbB4-dependent cell proliferation. Whereas further characterization is needed to evaluate the full therapeutic potential of these molecules, this drug discovery platform establishes reliable and scalable approaches for the discovery of ErbB4 inhibitors.

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Concepts Keywords
Agonist ERBB4
Melanoma Oncogenes
Melanomas ErbB
Mutant Neurotrophic factors
Partial Agonist Tyrosine kinase receptors
Partial Agonists Branches of biology
Phosphorylation Clinical metastatic melanoma
Receptor Tyrosine Kinase Tumors
Small Molecule Significant fraction melanomas
Throughput Neuregulin
Tyrosine Melanoma
Tyrosine phosphorylation


Type Source Name
disease MESH Development
disease MESH cancer
disease MESH melanoma
pathway KEGG Melanoma
drug DRUGBANK L-Tyrosine
disease MESH Leukemia
disease MESH noma
drug DRUGBANK Trestolone
drug DRUGBANK Amino acids
drug DRUGBANK Rasagiline
drug DRUGBANK Coenzyme M
drug DRUGBANK Ilex paraguariensis leaf
drug DRUGBANK Muplestim
pathway REACTOME Metabolism
drug DRUGBANK Naproxen
drug DRUGBANK Gefitinib
drug DRUGBANK Vincristine
drug DRUGBANK Trastuzumab
drug DRUGBANK Cetuximab
disease MESH infection
disease MESH mycoplasma infection
drug DRUGBANK Dimethyl sulfoxide
drug DRUGBANK Ademetionine
drug DRUGBANK Dabrafenib
drug DRUGBANK Trametinib
drug DRUGBANK Pembrolizumab
drug DRUGBANK Nivolumab
drug DRUGBANK Ipilimumab
disease MESH Breast Cancer
pathway KEGG Breast cancer
drug DRUGBANK Activated charcoal

Original Article

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