2. Academic Validation
  3. Aiming to Miss a Moving Target: Bromo and Extra Terminal Domain (BET) Selectivity in Constrained ATAD2 Inhibitors

Aiming to Miss a Moving Target: Bromo and Extra Terminal Domain (BET) Selectivity in Constrained ATAD2 Inhibitors

  • J Med Chem. 2018 Sep 27;61(18):8321-8336. doi: 10.1021/acs.jmedchem.8b00862.
Paul Bamborough,  Chun-Wa Chung,  Rebecca C Furze,  Paola Grandi 1,  Anne-Marie Michon 1,  Robert J Watson,  Darren J Mitchell,  Heather Barnett,  Rab K Prinjha,  Christina Rau 1,  Robert J Sheppard,  Thilo Werner 1,  Emmanuel H Demont
Affiliations

Affiliation

  • 1 Molecular Discovery Research, Cellzome GmbH , GlaxoSmithKline , Meyerhofstrasse 1 , 69117 Heidelberg , Germany.
PMID: 30226378 DOI: 10.1021/acs.jmedchem.8b00862
Abstract

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of its class. In our recent disclosure of the first chemical probe against this bromodomain, GSK8814 (6), we described the use of a conformationally constrained methoxy piperidine to gain selectivity over the BET bromodomains. Here we describe an orthogonal conformational restriction strategy of the piperidine ring to give potent and selective tropane inhibitors and show structural insights into why this was more challenging than expected. Greater understanding of why different rational approaches succeeded or failed should help in the future design of selectivity in the bromodomain family.

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