Inhibiting EGFR Dimerization Using Triazolyl-Bridged Dimerization Arm Mimics

Hanold, Laura E.; Oruganty, Krishnadev; Ton, Norman T.; Beedle, Aaron M.; Kannan, Natarajan; Kennedy, Eileen J.

doi:10.1371/journal.pone.0118796

Cited by 32 publications

(28 citation statements)

References 42 publications

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“…Constrained peptides have been developed to disrupt EGFR dimerization in order to block EGFR signaling pathways in cancer. One strategy focuses on the disruption of the receptor dimer by targeting the EGFR dimerization arm, a β-loop structure that stabilizes the EGFR dimer (Hanold, Oruganty, et al, 2015; Hanold, Watkins, et al, 2015; Mizuguchi, et al, 2012; Mizuguchi, et al, 2009; Toyama, Mizuguchi, Nomura, & Tamamura, 2016). In this approach, cyclic peptides mimicking the EGFR dimerization arm were developed to occlude the dimerization arm-binding site.…”

Section: Constrained Peptides As Allosteric Disruptors Of Kinasesmentioning

confidence: 99%

“…Multiple constraints have been applied to these peptides to improve activity and stability, including introduction of disulfide, selenylsulfide and triazolyl bridges. In some cases, cell-based inhibition was demonstrated with 10 μM IC 50 values (Hanold, Oruganty, et al, 2015; Toyama, et al, 2016). …”

Section: Constrained Peptides As Allosteric Disruptors Of Kinasesmentioning

confidence: 99%

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Targeting kinase signaling pathways with constrained peptide scaffolds

Hanold

Fulton

Kennedy

2017

Pharmacology & Therapeutics

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Kinases are amongst the largest families in the human proteome and serve as critical mediators of a myriad of cell signaling pathways. Since altered kinase activity is implicated in a variety of pathological diseases, kinases have become a prominent class of proteins for targeted inhibition. Although numerous small molecule and antibody-based inhibitors have already received clinical approval, several challenges may still exist with these strategies including resistance, target selection, inhibitor potency and in vivo activity profiles. Constrained peptide inhibitors have emerged as an alternative strategy for kinase inhibition. Distinct from small molecule inhibitors, peptides can provide a large binding surface area that allows them to bind shallow protein surfaces rather than defined pockets within the target protein structure. By including chemical constraints within the peptide sequence, additional benefits can be bestowed onto the peptide scaffold such as improved target affinity and target selectivity, cell permeability and proteolytic resistance. In this review, we highlight examples of diverse chemistries that are being employed to constrain kinase-targeting peptide scaffolds and highlight their application to modulate kinase signaling as well as their potential clinical implications.

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Section: Constrained Peptides As Allosteric Disruptors Of Kinasesmentioning

confidence: 99%

Section: Constrained Peptides As Allosteric Disruptors Of Kinasesmentioning

confidence: 99%

Targeting kinase signaling pathways with constrained peptide scaffolds

Hanold

Fulton

Kennedy

2017

Pharmacology & Therapeutics

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“…However, beta-loop/turn structures also play a significant role in various PPIs. Although there are many examples of constrained beta-loop/turns, including backbone-disulfide-stabilized mimetics [10], linkage of two beta-strands via a triazole bridge [11], cyclization of a linear precursor using a triazole bridge [12, 13], and hydrocarbon-linked turns [14], design of beta-loop mimics as PPI disruptors remains a challenge.…”

Section: Introductionmentioning

confidence: 99%

“…Recent efforts have focused on developing peptide disruptors that target the dimerization arm interface on EGFR [13, 22-24]. One example is a disulfide bridged peptide that maintains the beta-loop conformation as found in the dimerization arm of the protein [22, 23].…”

Section: Introductionmentioning

confidence: 99%

Design of a selenylsulfide-bridged EGFR dimerization arm mimic

Hanold

Katanski

Ton

et al. 2015

Bioorganic & Medicinal Chemistry

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The epidermal growth factor receptor (EGFR) dimerization arm is a key feature that stabilizes dimerization of the extracellular receptor, thereby mediating activation of the tyrosine kinase domain. Peptides mimicking this β-loop feature can disrupt dimer formation and kinase activation, yet these peptides lack structural constraints or contain redox sensitive disulfide bonds which may limit their stability in physiological environments. Selenylsulfide bonds are a promising alternative to disulfide bonds as they maintain much of the same structural and chemical behavior, yet they are inherently less prone to reduction. Herein, we describe the synthesis, stability and activity of selenylsulfide-bridged dimerization arm mimics. The synthesis was accomplished using an Fmoc-based strategy along with C-terminal labeling for improved overall yield. This selenylsulfide-bridged peptide displayed both proteolytic stability and structural stability even under reducing conditions, demonstrating the potential application of the selenylsulfide bond to generate redox stable β-loop peptides for disruption of protein-protein interactions.

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“…It is well known that amino acid segments excised from the proteine nvironment seldom reproduce the native conformation as they are unfolded in solution. [9] Recently,w er eported the use of interstrand 1-4 disubstituted 1,2,3 triazole as chemicalt ools to increaset he conformationala nd proteolytics tability in b-hairpin peptide. [3] The molecular factorsg overning b-hairpin folding and stability have been deeplys tudied, and molecular tools to reproduce stable b-hairpin peptides have been reported.…”

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confidence: 99%