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

DOI: 10.1016/j.ejmech.2020.112443 DOI Help

Authors: Sonia Martínez-González (Spanish National Cancer Research Centre (CNIO)) , Ana Belén García (Spanish National Cancer Research Centre (CNIO)) , M. Isabel Albarrán (Spanish National Cancer Research Centre (CNIO)) , Antonio Cebriá (Spanish National Cancer Research Centre (CNIO)) , Adrián Amezquita-Alves (Spanish National Cancer Research Centre (CNIO)) , Francisco Javier García-Campos (Spanish National Cancer Research Centre (CNIO)) , Jaime Martínez-Gago (Spanish National Cancer Research Centre (CNIO)) , Jorge Martínez-Torrecuadrada (Spanish National Cancer Research Centre (CNIO)) , Ines Munoz (Spanish National Cancer Research Centre (CNIO)) , Carmen Blanco-Aparicio (Spanish National Cancer Research Centre (CNIO)) , Joaquín Pastor (Spanish National Cancer Research Centre (CNIO))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry , VOL 201

State: Published (Approved)
Published: September 2020
Diamond Proposal Number(s): 16252

Abstract: 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.

Journal Keywords: CDK8; Type II inhibitors; P-loop flexibility; Selectivity; pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one scaffold

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 18/11/2020 09:00

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Cancer Drug Discovery Non-Communicable Diseases Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)