Substituted 2-(2-aminopyrimidin-4-yl)pyridine-4-carboxylates as potent inhibitors of JumonjiC domain-containing histone demethylases | Zendy

Martin Roatsch | Zendy; Dina Robaa | Zendy; Martin Pippel | Zendy; Joanne E. Nettleship | Zendy; Yamini Reddivari | Zendy; Louise E. Bird | Zendy; Inga Hoffmann | Zendy; Henriette Franz | Zendy; Raymond J. Owens | Zendy; Roland Schüle | Zendy; Ralf Flaig | Zendy; Wolfgang Sippl | Zendy; Manfred Jung | Zendy

Open Access

Substituted 2-(2-aminopyrimidin-4-yl)pyridine-4-carboxylates as potent inhibitors of JumonjiC domain-containing histone demethylases

Author(s) -

Martin Roatsch,

Dina Robaa,

Martin Pippel,

Joanne E. Nettleship,

Yamini Reddivari,

Louise E. Bird,

Inga Hoffmann,

Henriette Franz,

Raymond J. Owens,

Roland Schüle,

Ralf Flaig,

Wolfgang Sippl,

Manfred Jung

Publication year - 2016

Publication title -

future medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 0.708

H-Index - 69

eISSN - 1756-8927

pISSN - 1756-8919

DOI - 10.4155/fmc.15.188

Subject(s) - demethylase , chemistry , biochemistry , in vitro , histone , tripeptide , prodrug , virtual screening , stereochemistry , combinatorial chemistry , drug discovery , amino acid , gene

Background: Aberrant expression of iron(II)- and 2-oxoglutarate-dependent JumonjiC histone demethylases has been linked to cancer. Potent demethylase inhibitors are drug candidates and biochemical tools to elucidate the functional impact of demethylase inhibition. Methods & results: Virtual screening identified a novel lead scaffold against JMJD2A with low-micromolar potency in vitro. Analogs were acquired from commercial sources respectively synthesized in feedback with biological testing. Optimized compounds were transformed into cell-permeable prodrugs. A cocrystal x-ray structure revealed the mode of binding of these compounds as competitive to 2-oxoglutarate and confirmed kinetic experiments. Selectivity studies revealed a preference for JMJD2A and JARID1A over JMJD3. Conclusion: Virtual screening and rational structural optimization led to a novel scaffold for highly potent and selective JMJD2A inhibitors.

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