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

Daisuke Yasuda; Mao Nakajima; Akihiro Yuasa; Rika Obata; Kyoko Takahashi; Tomoyuki Ohe; Yoshinobu Ichimura; Masaaki Komatsu; Masayuki Yamamoto; Riyo Imamura; Hirotatsu Kojima; Takayoshi Okabe; Tetsuo Nagano; Tadahiko Mashino

doi:10.1016/j.bmcl.2016.10.083

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. Epub 2016 Oct 27.

Authors

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Naphthylamine / analogs & derivatives*
1-Naphthylamine / chemical synthesis
1-Naphthylamine / chemistry
1-Naphthylamine / pharmacology
Dose-Response Relationship, Drug
Humans
Kelch-Like ECH-Associated Protein 1 / antagonists & inhibitors*
Kelch-Like ECH-Associated Protein 1 / chemistry
Molecular Structure
NF-E2-Related Factor 2 / antagonists & inhibitors*
NF-E2-Related Factor 2 / chemistry
Naphthalenes / chemistry
Naphthalenes / pharmacology*
Protein Binding / drug effects
RNA-Binding Proteins / antagonists & inhibitors*
RNA-Binding Proteins / chemistry
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*
ras GTPase-Activating Proteins / antagonists & inhibitors*
ras GTPase-Activating Proteins / chemistry

Substances

2-acetonyl-1,4-bis((4-etoxybenzensulfonyl)amino)naphthalene
KEAP1 protein, human
Kelch-Like ECH-Associated Protein 1
NF-E2-Related Factor 2
Naphthalenes
P62 protein, human
RNA-Binding Proteins
Sulfonamides
ras GTPase-Activating Proteins
naphthalene
1-Naphthylamine