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Combined Proteomic and In Silico Target Identification Reveal a Role for 5-Lipoxygenase in Developmental Signaling Pathways

 
: Brand, S.; Roy, S.; Schröder, P.; Rathmer, B.; Roos, J.; Kapoor, S.; Patil, S.; Pommerenke, C.; Maier, T.; Janning, P.; Eberth, S.; Steinhilber, D.; Schade, D.; Schneider, G.; Kumar, K.; Ziegler, S.; Waldmann, H.

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Cell chemical biology 25 (2018), No.9, pp.1095-1106
ISSN: 2451-9456
English
Journal Article
Fraunhofer IME ()

Abstract
Identification and validation of the targets of bioactive small molecules identified in cell-based screening is challenging and often meets with failure, calling for the development of new methodology. We demonstrate that a combination of chemical proteomics with in silico target prediction employing the SPiDER method may provide efficient guidance for target candidate selection and prioritization for experimental in-depth evaluation. We identify 5-lipoxygenase (5-LO) as the target of the Wnt pathway inhibitor Lipoxygenin. Lipoxygenin is a non-redox 5-LO inhibitor, modulates the β-catenin-5-LO complex and induces reduction of both β-catenin and 5-LO levels in the nucleus. Lipoxygenin and the structurally unrelated 5-LO inhibitor CJ-13,610 promote cardiac differentiation of human induced pluripotent stem cells and inhibit Hedgehog, TGF-β, BMP, and Activin A signaling, suggesting an unexpected and yet unknown role of 5-LO in these developmental pathways.

: http://publica.fraunhofer.de/documents/N-541019.html