5F3E: Crystal Structure Of Human Kdm4a In Complex With Compound 54a

Citation:
Abstract
We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.
PDB ID: 5F3EDownload
MMDB ID: 135807
PDB Deposition Date: 2015/12/2
Updated in MMDB: 2016/03
Experimental Method:
x-ray diffraction
Resolution: 2.16  Å
Source Organism:
Similar Structures:
Biological Unit for 5F3E: monomeric; determined by author
Molecular Components in 5F3E
Label Count Molecule
Protein (1 molecule)
1
Lysine-specific Demethylase 4A(Gene symbol: KDM4A)
Molecule annotation
Chemicals (5 molecules)
1
2
2
1
3
1
4
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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