LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor (pages 6217–6221)
Peter G. K. Clark, Dr. Lucas C. C. Vieira, Dr. Cynthia Tallant, Dr. Oleg Fedorov, Dr. Dean C. Singleton, Dr. Catherine M. Rogers, Octovia P. Monteiro, James M. Bennett, Dr. Roberta Baronio, Dr. Susanne Müller, Dr. Danette L. Daniels, Jacqui Méndez, Prof. Dr. Stefan Knapp, Dr. Paul E. Brennan and Prof. Dr. Darren J. Dixon
Article first published online: 13 APR 2015 | DOI: 10.1002/anie.201501394
BRD7 and BRD9 are bromodomain proteins and part of some chromatin-remodeling complexes. A fragment lead was rapidly optimized through structure-based design and exploitation of a stereoselective nitro-Mannich/lactamization cascade process to give the first potent and selective BRD7/9 inhibitor, LP99. Treatment with LP99 led to displacement of BRD7 and BRD9 from chromatin and down-regulation of the pro-inflammatory cytokine IL-6.