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

DOI: 10.1016/j.bmc.2018.05.003 DOI Help

Authors: Laura E. Jennings (University of Oxford) , Matthias Schiedel (University of Oxford) , David S. Hewings (University of Oxford) , Sarah Picaud (Structural Genomics Consortium, University of Oxford) , Corentine M. C. Laurin (University of Oxford) , Paul A. Bruno (University of Michigan) , Joseph P. Bluck (University of Oxford) , Amy R. Scorah (University of Oxford) , Larissa See (University of Oxford) , Jessica K. Reynolds (University of Oxford) , Mustafa Moroglu (University of Oxford) , Ishna N. Mistry (University of Oxford) , Amy Hicks (University of Oxford) , Pavel Guzanov (University of Oxford) , James Clayton (University of Oxford) , Charles N. G. Evans (University of Oxford) , Giulia Stazi (Sapienza University of Rome) , Philip C. Biggin (University of Oxford) , Anna K. Mapp (University of Michigan) , Ester M. Hammond (University of Oxford) , Philip G. Humphreys (GlaxoSmithKline R&D) , Panagis Filippakopoulos (Structural Genomics Consortium, University of Oxford) , Stuart J. Conway (University of Oxford)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry

State: Published (Approved)
Published: May 2018
Diamond Proposal Number(s): 15433

Open Access Open Access

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).

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 23/05/2018 09:25


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)