Lookup NU author(s): Professor Mike Waring
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous programme, the compounds were optimised for BRD4 potency and physical properties. The optimised compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumour growth inhibition in xenograft studies. This compound was selected as the development candidate AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.
Author(s): Bradbury RH, Callis R, Carr GR, Chen H, Clark E, Feron L, Glossop S, Graham MA, Hattersley M, Jones C, Lamont SG, Ouvry G, Patel A, Patel J, Rabow AA, Roberts CA, Stokes S, Stratton N, Walker GE, Ward L, Whalley D, Whittaker D, Wrigley G, Waring MJ
Publication type: Article
Publication status: Published
Journal: Journal of Medicinal Chemistry
Online publication date: 15/08/2016
Acceptance date: 15/08/2016
Date deposited: 15/08/2016
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
Publisher: American Chemical Society
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