2. Academic Validation
  3. BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability

BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability

  • Bioorg Med Chem. 2018 Jul 15;26(11):2937-2957. doi: 10.1016/j.bmc.2018.05.003.
Laura E Jennings 1,  Matthias Schiedel 1,  David S Hewings 1,  Sarah Picaud 2,  Corentine M C Laurin 1,  Paul A Bruno 3,  Joseph P Bluck 4,  Amy R Scorah 1,  Larissa See 1,  Jessica K Reynolds 1,  Mustafa Moroglu 1,  Ishna N Mistry 5,  Amy Hicks 1,  Pavel Guzanov 1,  James Clayton 1,  Charles N G Evans 1,  Giulia Stazi 6,  Philip C Biggin 7,  Anna K Mapp 3,  Ester M Hammond 5,  Philip G Humphreys 8,  Panagis Filippakopoulos 2,  Stuart J Conway 9
Affiliations

Affiliations

  • 1 Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom.
  • 2 Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 3TA, United Kingdom.
  • 3 Department of Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, United States; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109-2216, United States; Program in Chemical Biology, University of Michigan, Ann Arbor, MI 48109-2216, United States.
  • 4 Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom; Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
  • 5 CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, United Kingdom.
  • 6 Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
  • 7 Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
  • 8 Epigenetics Discovery Performance Unit, GlaxoSmithKline R&D, Stevenage Hertfordshire SG1 2NY, United Kingdom.
  • 9 Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom. Electronic address: [email protected].
PMID: 29776834 DOI: 10.1016/j.bmc.2018.05.003
Abstract

Ligands for the bromodomain and extra-terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the RelA subunit of NF-κB, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t½ = 39.8 min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04. Molecular dynamics simulations assisted our understanding of the role played by an internal hydrogen bond in altering the affinity of this series of molecules for BRD4(1). OXFBD04 shows improved BRD4(1) affinity (IC50 = 166 nM), optimised physicochemical properties (LE = 0.43; LLE = 5.74; SFI = 5.96), and greater metabolic stability (t½ = 388 min).

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