Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor

Katherine S England; Anthony Tumber; Tobias Krojer; Giuseppe Scozzafava; Stanley S Ng; Michelle Daniel; Aleksandra Szykowska; KaHing Che; Frank von Delft; Nicola A Burgess-Brown; Akane Kawamura; Christopher J Schofield; Paul E Brennan

doi:10.1039/C4MD00291A

Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor

Medchemcomm. 2014 Dec 1;5(12):1879-1886. doi: 10.1039/C4MD00291A.

Authors

Katherine S England^#^{1

2}, Anthony Tumber^#^{1

3}, Tobias Krojer¹, Giuseppe Scozzafava^{1

3}, Stanley S Ng¹, Michelle Daniel¹, Aleksandra Szykowska¹, KaHing Che¹, Frank von Delft^{1

4}, Nicola A Burgess-Brown¹, Akane Kawamura^{2

5}, Christopher J Schofield², Paul E Brennan^{1

3}

Affiliations

¹ Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, UK.
² Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
³ Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7FZ, UK.
⁴ Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot, OX11 0QX, UK.
⁵ Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.

^# Contributed equally.

Abstract

A potent inhibitor of the JmjC histone lysine demethylase KDM2A (compound 35, pIC₅₀ 7.2) with excellent selectivity over representatives from other KDM subfamilies has been developed; the discovery that a triazolopyridine compound binds to the active site of JmjC KDMs was followed by optimisation of the triazole substituent for KDM2A inhibition and selectivity.

Abstract

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