TY - JOUR
T1 - Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity
AU - Yasuda, Daisuke
AU - Nakajima, Mao
AU - Yuasa, Akihiro
AU - Obata, Rika
AU - Takahashi, Kyoko
AU - Ohe, Tomoyuki
AU - Ichimura, Yoshinobu
AU - Komatsu, Masaaki
AU - Yamamoto, Masayuki
AU - Imamura, Riyo
AU - Kojima, Hirotatsu
AU - Okabe, Takayoshi
AU - Nagano, Tetsuo
AU - Mashino, Tadahiko
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Keap1
KW - Nrf2
KW - Protein-protein interaction inhibitor
KW - p62/Sqstm1
UR - http://www.scopus.com/inward/record.url?scp=85002251378&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85002251378&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2016.10.083
DO - 10.1016/j.bmcl.2016.10.083
M3 - Article
C2 - 27839920
AN - SCOPUS:85002251378
VL - 26
SP - 5956
EP - 5959
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 24
ER -