Novel indazole-based MKK7-TIPRL interaction inhibitors as TRAIL sensitizers = TRAIL sensitizers인 novel indazole 기반 MKK7-TIPRL 결합 저해제

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Title
Novel indazole-based MKK7-TIPRL interaction inhibitors as TRAIL sensitizers = TRAIL sensitizers인 novel indazole 기반 MKK7-TIPRL 결합 저해제
Author(s)
S Gu; M E Jung; Ji Yong Yoon; S E Yoon; Jeong Ju Lee; K Lee; G Choi; Nam-Soon Kim; M K Jeon
Bibliographic Citation
Bulletin of Korean Chemical Society, vol. 39, pp. 1125-1138
Publication Year
2018
Abstract
This work describes the process by which a metabolically unstable TRT?0002 compound exhibiting Tumor necrosis factor?related apoptosis?inducing ligand (TRAIL)?sensitizing activity for Huh7 cells at a high working concentration (40?μM) is converted to more potent and metabolically improved analogues by modifying the 5?amino group and the 1?aryl moiety in the 1H?indazole skeleton. The efforts enabled us to identify 5?sulfonamido derivatives, TRT?0029 and TRT?0173 compounds, working at lower concentrations (10 and 20?μM, respectively) and with improved metabolic stabilities. As reported previously by us, co?treating cultured Huh7 cells with either TRT?0029 or TRT?0173 and TRAIL resulted in TRAIL?induced apoptosis due to the inhibition of the MKK7?TOR signaling pathway regulator?like (TIPRL) interaction and subsequent phosphorylation of MKK7 and JNK. In addition, the injection of TRT?0029 or TRT?0173 compound suppressed tumor growth in combination with TRAIL in an in vivo hepatocellular carcinoma (HCC) mouse xenograft model. TRT?0029 and TRT?0173 compounds and the relevant structure?activity relationship can provide an insight into further study on optimization of potency and metabolic stability.
Keyword
ApoptosisIndazoleSensitizerTOR signaling pathway regulator-likeTumor necrosis factor-related apoptosis-inducing ligand
ISSN
0253-2964
Publisher
Wiley
DOI
http://dx.doi.org/10.1002/bkcs.11561
Type
Article
Appears in Collections:
Division of Biomedical Research > Rare Disease Research Center > 1. Journal Articles
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