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

  • Bioorg Med Chem Lett. 2016 Dec 15;26(24):5956-5959. doi: 10.1016/j.bmcl.2016.10.083.
Daisuke Yasuda  1 ,  Mao Nakajima  1 ,  Akihiro Yuasa  1 ,  Rika Obata  1 ,  Kyoko Takahashi  1 ,  Tomoyuki Ohe  2 ,  Yoshinobu Ichimura  3 ,  Masaaki Komatsu  3 ,  Masayuki Yamamoto  4 ,  Riyo Imamura  5 ,  Hirotatsu Kojima  5 ,  Takayoshi Okabe  5 ,  Tetsuo Nagano  5 ,  Tadahiko Mashino  6
Affiliations
  • 1. Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan.
  • 2. Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan. Electronic address: [email protected].
  • 3. Department of Biochemistry, School of Medicine, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata-shi, Niigata, Japan.
  • 4. Department of Medical Biochemistry, Tohoku University School of Medicine, 2-1 Seiryomachi, Aoba-ku, Sendai-shi, Miyagi, Japan.
  • 5. Drug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
  • 6. Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan. Electronic address: [email protected].
PMID: 27839920 DOI: 10.1016/j.bmcl.2016.10.083
Abstract

The Keap1-Nrf2 system is involved not only in biological defense but also in malignancy progression and chemoresistance. The ubiquitin-binding protein p62/Sqstm1 (p62), which is highly expressed in several cancers, competes with Nrf2 for Keap1 binding, leading to activation of Nrf2-mediated gene expression and survival of Cancer cells. We had previously identified an inhibitor for the Keap1-phosphorylated-p62 (p-p62) protein-protein interaction (PPI), the acetonyl naphthalene derivative K67. In this study, we established facile synthetic routes for K67 and derivatives with various side chains on the C-2 position of naphthalene ring. K67 possessed high selectivity in the inhibition of Keap1-p-p62. Other derivatives showed potent Keap1-Nrf2 and Keap1-p-p62 PPI inhibitory activities, though the selectivity between the two activities was lower than K67.

Keywords
Keap1; Nrf2; Protein-protein interaction inhibitor; p62/Sqstm1.
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-111126
    K67
    98.26%, Keap1/S349-p-p62 Interaction Inhibitor
    target: p62; Keap1-Nrf2
    Research Areas: Cancer