Pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives as CDK8 inhibitors

• Published in: European journal of medicinal chemistry Vol. 201; p. 112443
• Main Authors: Martínez-González, Sonia, García, Ana Belén, Albarrán, M. Isabel, Cebriá, Antonio, Amezquita-Alves, Adrián, García-Campos, Francisco Javier, Martínez-Gago, Jaime, Martínez-Torrecuadrada, Jorge, Muñoz, I.G., Blanco-Aparicio, Carmen, Pastor, Joaquín
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-09-2020
• Subjects: CDK8; Cell Line, Tumor; Cyclin-Dependent Kinase 8 - antagonists & inhibitors; Drug Design; Humans; Molecular Structure; Oxazepines - chemical synthesis; Oxazepines - pharmacology; P-loop flexibility; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Pyridines - chemical synthesis; Pyridines - pharmacology; pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one scaffold; Selectivity; Sorafenib - analogs & derivatives; Sorafenib - pharmacology; Structure-Activity Relationship; Type II inhibitors; CDK8; Selectivity; Type II inhibitors; pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one scaffold; P-loop flexibility
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112443

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.
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•Design of novel type II tricyclic CDK8 inhibitors based on Sorafenib.•Binding of inhibitors to CDK8 by filling an unexplored cavity via displacement of its flexible P-loop.•Potent and highly selective pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one based CDK8 inhibitors.