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Characterization of the molecular mechanism of 5-lipoxygenase inhibition by 2-aminothiazoles

: Kretschmer, S.B.M.; Woltersdorf, S.; Vogt, D.; Lillich, F.F.; Rühl, M.; Karas, M.; Maucher, I.V.; Roos, J.; Häfner, A.-K.; Kaiser, A.; Wurglics, M.; Schubert-Zsilavecz, M.; Angioni, C.; Geisslinger, G.; Stark, H.; Steinhilber, D.; Hofmann, B.


Biochemical pharmacology 123 (2017), pp.52-62
ISSN: 0006-2952
ISSN: 1873-2968
Journal Article
Fraunhofer IME ()

5-Lipoxygenase (5-LO, EC1.13.11.34) has been implicated in the pathogenesis of inflammatory and immune diseases. Recently, aminothiazole comprising inhibitors have been discovered for this valuable target. Yet, the molecular mode of action of this class of substances is only poorly understood. Here, we present the detailed molecular mechanism of action of the compound class and the in vitro pharmacological profile of two lead compounds ST-1853 and ST-1906. Mechanistic studies with recombinant proteins as well as intact cell assays enabled us to define this class as a novel type of 5-LO inhibitors with unique characteristics. The parent compounds herein presented a certain reactivity concerning oxidation and thiol binding: Unsubstituted aminophenols bound covalently to C159 and C418 of human 5-LO. Yet, dimethyl substitution of the aminophenol prevented this reactivity and slowed down phase II metabolism. Both ST-1853 and ST-1906 confirmed their lead likeness by retaining their high potency in physiologically relevant 5-LO activity assays, high metabolic stability, high specificity and non-cytotoxicity.