Rational Design for the Development of Epidermal Growth Factor Receptor Antagonists

Zoelen, E.J.J. van; Lenferink, Anne E.G.; Kramer, R.H.; Poll, Monique L.M. van de

doi:10.1016/s0344-0338(96)80098-7

Cited by 8 publications

(4 citation statements)

References 19 publications

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“…However, it is also apparent that the intrinsic biological activity of the EGF molecule requires additional areas of sequence, as shown by our findings that the penta- and decapeptides were inactive. Identification of which residues outside of the C terminal region of the EGF molecule are vital for biological activity is difficult and complex 24. Part of this complexity results from the fact that, in common with many other biologically active peptides, Cys-Cys disulphide bridging within the EGF molecule brings amino acid residues which appear distant on the primary sequence into close proximity in its correctly folded tertiary state.…”

Section: Discussionmentioning

confidence: 99%

Potency and stability of C terminal truncated human epidermal growth factor

Calnan

Fagbemi²,

Berlanga‐Acosta³

et al. 2000

Gut

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Section: Discussionmentioning

confidence: 99%

Potency and stability of C terminal truncated human epidermal growth factor

Calnan

Fagbemi²,

Berlanga‐Acosta³

et al. 2000

Gut

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“…The C-loop of EGF domains also contains critical residues for EGFR activation (9,13,67). Both Spitz and Argos contain the two key amino acids (Gly-39 and Arg-41 from human EGF; Fig.…”

Section: Discussionmentioning

confidence: 99%

“…(Drosophila diverged from vertebrates 600 -1000 million years ago). We are more hopeful of engineering an antagonist based on known mammalian ligands, as has been tried by several groups (9,14,32,33), and our goal is to exploit Argos and Spitz to gain the necessary insight into the mechanisms of EGFR activation and inhibition.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Analysis of Argos Structure-Function

Howes

Wasserman

Freeman

1998

Journal of Biological Chemistry

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The Drosophila Argos protein is the only known extracellular inhibitor of the epidermal growth factor receptor (EGFR). It is structurally related to the activating ligands, in that it is a secreted protein with a single epidermal growth factor (EGF) domain. To understand the mechanism of Argos inhibition, we have investigated which regions of the protein are essential. A series of deletions were made and tested in vivo; furthermore, by analyzing chimeric proteins between Argos and the activating ligand, Spitz (a transforming growth factor-␣-like factor), we have examined what makes one inhibitory and the other activating. Our results reveal that Argos has structural requirements that differ from all known EGFR activating ligands; domains flanking the EGF domain are essential for its function. We have also defined the important regions of the atypical Argos EGF domain. The extended B-loop is necessary, whereas the C-loop can be replaced with the equivalent Spitz region without substantially affecting Argos function. Comparison of the argos genes from Drosophila melanogaster and the housefly, Musca domestica, supports our structure-function analysis. These studies are a prerequisite for understanding how Argos inhibits the Drosophila EGFR and provide a basis for designing mammalian EGFR inhibitors. The epidermal growth factor receptor (EGFR)1 controls many aspects of animal growth, development, and cell proliferation (1). How these different roles are coordinated and their relative importance in normal development is not yet well understood, but it is clear that overactivation of the receptor in mammals is implicated in many forms of cancer (2-5). This overactivation can be caused by amplification of the receptor gene, by activating mutations in the receptor, or frequently by overexpression of activating ligands, which causes inappropriate autocrine signaling. The EGFR is a tyrosine kinase; it has an extracellular ligand binding domain and an intracellular kinase domain. As with other receptor tyrosine kinases, it forms dimers upon activation, and these then transphosphorylate each other, causing the activation of downstream signal transduction pathways (6). There are four members of the EGFR family in mammals (ErbB1-ErbB4), and they act in a complex set of overlapping functions, both as homo-and heterodimers (7). They are activated by several classes of ligand, including EGF itself, transforming growth factor-␣ (TGF␣), neuregulins, and others. The motif responsible for receptor activation in all known ligands is an EGF domain, comprising six characteristically spaced cysteines and a few other essential amino acids (8). Antagonists of the EGFR might have therapeutic potential, and much effort has been made to understand ligand binding and activation, to help design such inhibitors (9 -14). Although several important regions have been identified, effective antagonists have remained elusive because of the apparent inability to uncouple receptor binding and activation; all mutants that still bind efficiently are acti...

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“…The growth factors like TGF-α and EGF bind with similar high affinity to the human EGF receptor [11] and have been implicated in cancer development and progression through autocrine and paracrine pathways [12,13]. The activation of EGFR initiates a cascade of signaling mechanisms such as the recruitment of mitogen activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3 kinase) pathways [14].…”

Section: Introductionmentioning

confidence: 99%

Modulation of key signal transduction molecules by a novel peptide combination effective for the treatment of gastrointestinal carcinomas

et al. 2008

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We have reported earlier a novel combination of four structurally designed synthetic neuropeptide analogs of vasoactive intestinal peptide (VIP), bombesin, substance P and somatostatin, code-named DRF 7295 which have anti-tumor efficacy for adenocarcinomas in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). The discovery, synthesis, in vitro and in vivo efficacy was reported (Jaggi et al., Invest New Drugs, 2008). Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to most sensitive to DRF7295 in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). We have further investigated and report here the modulation of cellular signaling in gastrointestinal carcinomas by DRF 7295, which may be mediating its observed anticancer activity in these cancer types. DRF 7295 inhibits the binding of specific neuropeptides initiating a cascade of cellular signaling events leading to programmed cell death. It down regulates the second messenger cAMP, epidermal growth factor (EGF) dependent proliferation and the phosphorylated MAP Kinase pERK1/2 in gastrointestinal carcinomas, thus depriving the tumour cells of critical pro-proliferative cellular signals. It triggers bcl2 and Caspase 3 dependent apoptotic cell death and induces p53 tumor suppressor protein in the treated carcinoma cells in vitro. It has significant anti-angiogenic potential as reflected in the inhibition of tube like formation in the endothelial cells and down regulation of VEGF levels. Tumour xenograft studies confirmed the in vivo efficacy of DRF 7295 for gastrointestinal carcinomas (Jaggi et al., Invest New Drugs, 2008). The Phase I clinical trials have shown DRF 7295 to be well tolerated and devoid of systemic toxicities of the conventional cytotoxics (Mukherjee et al., Phase I dose escalating study of DRF7295: a new class of peptide based drugs. "Abstract" ASCO ID:948, 2003). The drug may have a promising role in disease stabilization in colorectal and other cancers. Thus DRF 7295 is a novel targeted drug in the class of signal transduction modulators, with potential for treatment of gastrointestinal carcinomas.

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Rational Design for the Development of Epidermal Growth Factor Receptor Antagonists

Cited by 8 publications

References 19 publications

Potency and stability of C terminal truncated human epidermal growth factor

Potency and stability of C terminal truncated human epidermal growth factor

In Vivo Analysis of Argos Structure-Function

Modulation of key signal transduction molecules by a novel peptide combination effective for the treatment of gastrointestinal carcinomas

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