ABSTRACT
The Keap1-Nrf2 system is an attractive target for drug discovery regarding various unmet medical needs. Only covalent inhibitors for protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 have been approved or are under clinical trials, but such electrophilic compounds lack selectivity. Therefore, specific non-covalent Keap1-Nrf2 PPI inhibitors are expected to be safer Nrf2 activators. We found a novel class of non-covalent Keap1-Nrf2 PPI inhibitor that has a benzo[g]indole skeleton and an indole-3-hydroxamic acid moiety and that exhibits significant PPI inhibitory activity. Additionally, the benzo[g]indole-3-carbohydrazide derivatives were newly prepared. The benzo[g]indole derivatives showed a stronger Keap1-Nrf2 PPI inhibitory activity than Cpd16, a previously reported non-covalent PPI inhibitor. Moreover, most of the PPI inhibitors showed a high metabolic stability in a human microsome system with a low cytotoxicity against HepG2 cell lines, which suggests that novel benzo[g]indole-type Keap1-Nrf2 PPI inhibitors are expected to be biological tools or lead compounds for Nrf2 activators.
Subject(s)
Indoles/chemistry , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , Cell Survival/drug effects , Drug Evaluation, Preclinical , Hep G2 Cells , Humans , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/chemistry , Hydroxamic Acids/toxicity , Indoles/chemical synthesis , Indoles/toxicity , Inhibitory Concentration 50 , Kelch-Like ECH-Associated Protein 1/antagonists & inhibitors , Microsomes, Liver/metabolism , NF-E2-Related Factor 2/antagonists & inhibitors , Protein Interaction Domains and MotifsABSTRACT
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.
Subject(s)
1-Naphthylamine/analogs & derivatives , Kelch-Like ECH-Associated Protein 1/antagonists & inhibitors , NF-E2-Related Factor 2/antagonists & inhibitors , Naphthalenes/pharmacology , RNA-Binding Proteins/antagonists & inhibitors , Sulfonamides/pharmacology , ras GTPase-Activating Proteins/antagonists & inhibitors , 1-Naphthylamine/chemical synthesis , 1-Naphthylamine/chemistry , 1-Naphthylamine/pharmacology , Dose-Response Relationship, Drug , Humans , Kelch-Like ECH-Associated Protein 1/chemistry , Molecular Structure , NF-E2-Related Factor 2/chemistry , Naphthalenes/chemistry , Protein Binding/drug effects , RNA-Binding Proteins/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , ras GTPase-Activating Proteins/chemistryABSTRACT
We present a proposal of a partial reconfiguration architecture for optically reconfigurable gate arrays and present an 11,424 gate dynamic optically reconfigurable gate array VLSI chip that was fabricated on a 96.04 mm(2) chip using an 0.35 µm three-metal complementary metal oxide semiconductor process technology. The fabricated VLSI chip achieved a 2.21 µs partial reconfiguration.
ABSTRACT
We propose an optical buffering technique for a programmable gate array under a space radiation environment. The technique allows rapid recovery of a programmable device that is damaged by high-energy charged particles. The technique uses invalid configuration data, including error bits that have already been damaged by the particles, while the configuration data are transferred using wireless communications and are retained on electronically erasable, programmable read-only, or static random-access-memory devices.
