Details

Autor(en) / Beteiligte

• Clark, Peter G. K.
• Vieira, Lucas C. C.
• Tallant, Cynthia
• Fedorov, Oleg
• Singleton, Dean C.
• Rogers, Catherine M.
• Monteiro, Octovia P.
• Bennett, James M.
• Baronio, Roberta
• Müller, Susanne
• Daniels, Danette L.
• Méndez, Jacqui
• Knapp, Stefan
• Brennan, Paul E.
• Dixon, Darren J.

Titel

LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor

Ist Teil von

• Angewandte Chemie International Edition, 2015-05, Vol.54 (21), p.6217-6221

Auflage

International ed. in English

Ort / Verlag

Weinheim: WILEY-VCH Verlag

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• The bromodomain‐containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin‐remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone‐fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure‐based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity‐building nitro‐Mannich/lactamization cascade processes allowed for early structure–activity relationship studies whereas an enantioselective organocatalytic nitro‐Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro‐inflammatory cytokine secretion. 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.