288148-78-7Relevant academic research and scientific papers
Hepatitis C viral IRES inhibition by phenazine and phenazine-like molecules
Wang, Wuyi,Preville, Patrice,Morin, Nicolas,Mounir, Samir,Cai, Weizhong,Siddiqui, M. Arshad
, p. 1151 - 1154 (2000)
An in vitro assay based on the expression of Fluci reporter gene under the translational control of HCV IRES was used to evaluate and screen compound libraries. A structure-activity relationship study on a phenazine hit was conducted. Our data suggest that an intact phenazine or phenazine-like core with two distal polar substitutions is crucial for potency. (C) 2000 Elsevier Science Ltd. All rights reserved.
Pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives as CDK8 inhibitors
Blanco-Aparicio, Carmen,Albarrán, M. Isabel,Amezquita-Alves, Adrián,Cebriá, Antonio,García, Ana Belén,García-Campos, Francisco Javier,Martínez-Gago, Jaime,Martínez-González, Sonia,Martínez-Torrecuadrada, Jorge,Mu?oz, Inés,Pastor, Joaquín
, (2020)
CDK8 is a cyclin-dependent kinase that forms part of the mediator complex, and modulates the transcriptional output from distinct transcription factors involved in oncogenic control. Overexpression of CDK8 has been observed in various cancers, representing a potential target for developing novel CDK8 inhibitors in cancer therapeutics. In the course of our investigations to discover new CDK8 inhibitors, we designed and synthesized tricyclic pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives, by introduction of chemical complexity in the multi-kinase inhibitor Sorafenib taking into account the flexibility of the P-loop motif of CDK8 protein observed after analysis of structural information of co-crystallized CDK8 inhibitors. In vitro evaluation of the inhibitory activity of the prepared compounds against CDK8 led us to identify compound 2 as the most potent inhibitor of the series (IC50 = 8.25 nM). Co-crystal studies and the remarkable selectivity profile of compound 2 are presented. Compound 2 showed moderate reduction of phosphorylation of CDK8 substrate STAT1 in cells, in line with other reported Type II CDK8 inhibitors. We propose herein an alternative to find a potential therapeutic use for this chemical series.
