BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability
| Autor: | Ishna N. Mistry, Philip G. Humphreys, Panagis Filippakopoulos, Amy Hicks, Pavel Guzanov, Laura E. Jennings, Larissa See, Jessica K. Reynolds, Amy R. Scorah, Matthias Schiedel, Anna K. Mapp, James Clayton, David S. Hewings, Paul A. Bruno, Mustafa Moroglu, Charles N. G. Evans, Corentine M.C. Laurin, Stuart J. Conway, Joseph P. Bluck, Ester M. Hammond, Giulia Stazi, Sarah Picaud, Philip C. Biggin |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
BRD4 Protein subunit Blotting Western Clinical Biochemistry Pharmaceutical Science Cell Cycle Proteins Molecular Dynamics Simulation Crystallography X-Ray Ligands Heterocyclic Compounds 4 or More Rings Biochemistry Histone H4 Inhibitory Concentration 50 Structure-Activity Relationship 03 medical and health sciences Drug Stability Drug Discovery Humans Structure–activity relationship Molecule Luciferases Molecular Biology Molecular Structure Chemistry Ligand Hydrogen bond Organic Chemistry Nuclear Proteins Combinatorial chemistry 3. Good health Bromodomain 030104 developmental biology MCF-7 Cells Molecular Medicine Biological Assay Transcription Factors |
| Zdroj: | Bioorganic & Medicinal Chemistry |
| ISSN: | 0968-0896 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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