Synthesis and testing of inhibitors for jumonjiC domain-containing histone demethylases

Abstract: JumonjiC domain-containing histone demethylases (JmjC-KDMs) are epigenetic enzymes capable of oxidatively removing methyl marks from histone and non-histone proteins in an iron(II)- and 2-oxoglutarate-dependent mechanism. Their involvement in various diseases, particularly cancer, has been shown in numerous studies.
Diverse compounds based on known KDM inhibitors were synthesized or acquired from collaboration partners and evaluated in this work. Biochemical testing was performed using two orthogonal KDM4A assays. This workflow allowed iterative compound optimization based on activity measurements. Two main strategies were employed in the inhibitor development, namely the generation of bioisosteres of published inhibitors and the synthesis of analogs of the clinically approved iron-chelator deferasirox. The first approach yielded two scaffolds with IC50 values in the micromolar range, which both contain tetrazoles as bioisosteric replacement for carboxylic acids. The second approach resulted in five different core structures – triazoles, thiazoles, oxazoles, pyrazoles and imidazoles. An inhibitor potency in the single-digit micromolar range could be achieved for numerous compounds and distinctive structure activity relationships were uncovered. Weak selectivity for KDM4A over KDM5A and KDM6B was accomplished for a thiazole compound. Antiproliferative cellular activity on an oesophageal cancer cell line was shown and on-target effects on KDM4 were revealed using immunofluorescence measurements for selected compounds. The synthesis of two fluorescently and one biotin-labelled derivative and their high activity towards KDM4A provide a starting point for further in vitro and possibly also in vivo studies. The newly discovered inhibitors, particularly the deferasirox-based compounds, may serve as valuable tool compounds for the study of the physiological and pathophysiological roles of KDMs and may be used for the investigation of the therapeutic potential of this enzyme class

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Universität Freiburg, Dissertation, 2020

Klassifikation und Themen

• Schlagwort: Inhibitor

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2021
• Urheber: Wenzler, Sandra
• Beteiligte Personen und Organisationen: Jung, Manfred ; Albert-Ludwigs-Universität Freiburg. Fakultät für Chemie und Pharmazie

Weitere Informationen

• DOI: 10.6094/UNIFR/176077
• URN: urn:nbn:de:bsz:25-freidok-1760777
• Rechteinformation: Kein Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 14.08.2025, 10:53 MESZ