Reference Detail

Ref Type

Journal Article

PMID

(24696502)

Authors

Colzani M, Noberini R, Romanenghi M, Colella G, Pasi M, Fancelli D, Varasi M, Minucci S, Bonaldi T

Title

Quantitative chemical proteomics identifies novel targets of the anti-cancer multi-kinase inhibitor E-3810.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular & cellular proteomics : MCP	13	6	2014 Jun	1495-509	Mol Cell Proteomics

URL

Abstract Text

Novel drugs are designed against specific molecular targets, but almost unavoidably they bind non-targets, which can cause additional biological effects that may result in increased activity or, more frequently, undesired toxicity. Chemical proteomics is an ideal approach for the systematic identification of drug targets and off-targets, allowing unbiased screening of candidate interactors in their natural context (tissue or cell extracts). E-3810 is a novel multi-kinase inhibitor currently in clinical trials for its anti-angiogenic and anti-tumor activity. In biochemical assays, E-3810 targets primarily vascular endothelial growth factor and fibroblast growth factor receptors. Interestingly, E-3810 appears to inhibit the growth of tumor cells with low to undetectable levels of these proteins in vitro, suggesting that additional relevant targets exist. We applied chemical proteomics to screen for E-3810 targets by immobilizing the drug on a resin and exploiting stable isotope labeling by amino acids in cell culture to design experiments that allowed the detection of novel interactors and the quantification of their dissociation constant (Kd imm) for the immobilized drug. In addition to the known target FGFR2 and PDGFRα, which has been described as a secondary E-3810 target based on in vitro assays, we identified six novel candidate kinase targets (DDR2, YES, LYN, CARDIAK, EPHA2, and CSBP). These kinases were validated in a biochemical assay and-in the case of the cell-surface receptor DDR2, for which activating mutations have been recently discovered in lung cancer-cellular assays. Taken together, the success of our strategy-which integrates large-scale target identification and quality-controlled target affinity measurements using quantitative mass spectrometry-in identifying novel E-3810 targets further supports the use of chemical proteomics to dissect the mechanism of action of novel drugs.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Lucitanib	Lucitanib	6	5

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Lucitanib		E-3810\|AL3810	DDR1 Inhibitor 10 DDR2 inhibitor 7 FGFR1 Inhibitor 28 FGFR2 Inhibitor 23 PDGFR-alpha Inhibitor 9 VEGFR Inhibitor (Pan) 36	Lucitanib (E-3810) is a multi-tyrosine kinase receptor inhibitor of VEGFR 1-3, DDR2, PDGFRA, and FGFR1-2, that may inhibit tumor angiogenesis, prevent tumor cell proliferation, and induce tumor cell death (PMID: 27988457, PMID: 24696502, PMID: 31619444).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References