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.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
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 Hdoi
10.1016/j.chembiol.2018.05.016subject
Has Abstractpub_date
2018-09-20 00:00:00pages
1095-1106.e23issue
9eissn
2451-9456issn
2451-9448pii
S2451-9456(18)30187-9journal_volume
25pub_type
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