Optimization of 3,5-Dimethylisoxazole Derivatives as Potent Bromodomain Ligands

David S. Hewings†‡, Oleg Fedorov‡, Panagis Filippakopoulos‡, Sarah Martin‡, Sarah Picaud‡, Anthony Tumber‡, Christopher Wells‡, Monica M. Olcina§, Katherine Freeman†, Andrew Gill∥, Alison J. Ritchie∥, David W. Sheppard∥, Angela J. Russell†, Ester M. Hammond§, Stefan Knapp‡, Paul E. Brennan‡, and Stuart J. Conway*†

^† Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.

^‡ Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 3TA, U.K.

^§ Department of Oncology, Cancer Research UK/MRC Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, U.K.

^∥ BioFocus, Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, U.K.

J. Med. Chem., 2013, 56 (8), pp 3217–3227

DOI: 10.1021/jm301588r

Publication Date (Web): March 21, 2013

*Telephone: +44 (0)1865 285 109. Fax: +44 (0)1865 285 002. E-mail: stuart.conway@chem.ox.ac.uk.

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Accession Codes

Atomic coordinates and structure factors for the reported crystal structures have been deposited with the Protein Data Bank under accession codes 4J0R [(R)-8] and 4J0S [(S)-8].

Abstract

The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.

Supporting Information

Enantiomeric purity determination of 8 by chiral HPLC, stability of (+)-8 in aqueous buffer, SPR steady state affinity analysis of (R)- and (S)-8 binding to BRD4(1), comparison of the BRD4(1) and CREBBP bromodomains, BRD4(1) and CREBBP bromodomain sequence alignment, MTS viability assays for MV4;11, A549, and H1975 cells, steady state analysis parameters for (R)- and (S)-8 binding to BRD4(1), crystallographic information, further general experimental details, synthesis and characterization of compounds 10, 11, 18–20, and further characterization (¹³C and ¹⁹F NMR, elemental analysis) for compounds 8, 9, 12–17, 21–23. This material is available free of charge via the Internet at http://pubs.acs.org.

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Optimization of 3,5-Dimethylisoxazole Derivatives as Potent Bromodomain Ligands

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