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Oligopeptide Competition Assay for Phosphorylation Site Determination
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Oligopeptide Competition Assay for Phosphorylation Site Determination

Published on: May 18, 2017

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Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory

Daisuke Yasuda1, Mao Nakajima1, Akihiro Yuasa1

  • 1Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan.

Bioorganic & Medicinal Chemistry Letters
|November 15, 2016
PubMed

Insights

Researchers developed new inhibitors targeting the Keap1-Nrf2 pathway, crucial in cancer progression and chemoresistance. These compounds, derived from K67, show promise in blocking cancer cell survival mechanisms by inhibiting key protein-protein interactions.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • The Keap1-Nrf2 pathway regulates biological defense but also promotes cancer malignancy and chemoresistance.
  • Overexpressed p62/Sqstm1 (p62) in cancers activates Nrf2 by competing with Nrf2 for Keap1 binding, enhancing cancer cell survival.

Purpose of the Study:

  • To synthesize and evaluate novel derivatives of the Keap1-p-p62 protein-protein interaction (PPI) inhibitor K67.
  • To assess the inhibitory activity and selectivity of these derivatives against Keap1-p-p62 and Keap1-Nrf2 PPIs.

Main Methods:

  • Facile synthetic routes were established for K67 and its derivatives with modifications at the C-2 position of the naphthalene ring.
  • In vitro assays were used to determine the inhibitory potential and selectivity of the synthesized compounds against specific PPIs.

Main Results:

  • K67 demonstrated high selectivity for inhibiting the Keap1-phosphorylated-p62 (p-p62) PPI.
  • Several K67 derivatives exhibited potent inhibition of both Keap1-Nrf2 and Keap1-p-p62 PPIs.
  • The selectivity between Keap1-Nrf2 and Keap1-p-p62 inhibition was reduced in the K67 derivatives compared to K67.

Conclusions:

  • Novel K67 derivatives offer potent inhibition of critical PPIs in the Keap1-Nrf2 pathway.
  • These compounds represent potential therapeutic agents for cancers where the Keap1-Nrf2 pathway is implicated in malignancy and chemoresistance.
  • Further optimization may be needed to balance potency and selectivity for therapeutic development.
Keywords:
Keap1Nrf2Protein-protein interaction inhibitorp62/Sqstm1

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