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. Epub 2018 Sep 18.


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.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / antagonists & inhibitors*
  • Cell Cycle Proteins
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nuclear Proteins / antagonists & inhibitors*
  • Protein Conformation
  • Protein Domains
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors*


  • BRD4 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Small Molecule Libraries
  • Transcription Factors
  • ATAD2 protein, human
  • ATPases Associated with Diverse Cellular Activities