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Machine-assisted synthesis of modulators of the histone reader BRD9 using flow methods of chemistry and frontal affinity chromatography

Lucie Guetzoyan,a Richard J. Ingham,a Nikzad Nikbin,a Julien Rossignol,a Michael Wolling,a Mark Baumert,b Nicola A. Burgess-Brown,c Claire M. Strain- Damerell,c Leela Shrestha,c Paul E. Brennan,c Oleg Fedorov,c Stefan Knappc and Steven V. Ley*a

aInnovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, UK.

bAdvion Ltd, Harlow Enterprise Hub, Edinburgh Way, Harlow, Essex, CM20 2NQ, UK cStructural Genomics Consortium and Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7FZ, UK

A combination of conventional organic synthesis, remotely monitored flow synthesis and bioassay platforms, were used for the evaluation of novel inhibitors targeting bromodomains outside the wellstudied bromodomain and extra terminal (BET) family, here exemplified by activity measurements on the bromodomain of BRD9 protein, a component of some tissue-specific SWi/SNF chromatin remodelling complexes. The Frontal Affinity Chromatography combined with Mass Spectrometry (FAC-MS) method proved to be reliable and results correlated well with an independent thermal shift assay.