2. Academic Validation
  3. Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity

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

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: ohe-tm@pha.keio.ac.jp.
  • 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: mashino-td@pha.keio.ac.jp.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-111126
    98.26%, Keap1/S349-p-p62 Interaction Inhibitor