title: Luciferin and derivatives as a DYRK selective scaffold for the design of protein kinase inhibitors.
abstract: D-Luciferin is widely used as a substrate in luciferase catalysed bioluminescence assays for in vitro studies. However, little is known about cross reactivity and potential interference of D-luciferin with other enzymes. We serendipitously found that firefly luciferin inhibited the CDK2/Cyclin A protein kinase. Inhibition profiling of D-luciferin over a 103-protein kinase panel showed significant inhibition of a small set of protein kinases, in particular the DYRK-family, but also other members of the CMGC-group, including ERK8 and CK2. Inhibition profiling on a 16-member focused library derived from D-luciferin confirms that D-luciferin represents a DYRK-selective chemotype of fragment-like molecular weight. Thus, observation of its inhibitory activity and the initial SAR information reported here promise to be useful for further design of protein kinase inhibitors with related scaffolds.
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
authors.forename: Ulli
authors.initials: U
authors.lastname: Rothweiler
authors.affiliation: Lytix Biopharma AS, P.O. Box 6447, Tromsø Science Park, N-9294 Tromsø, Norway.
authors.forename: Jonas
authors.initials: J
authors.lastname: Eriksson
authors.affiliation: Lytix Biopharma AS, P.O. Box 6447, Tromsø Science Park, N-9294 Tromsø, Norway; Department of Chemistry, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
authors.forename: Wenche
authors.initials: W
authors.lastname: Stensen
authors.affiliation: Lytix Biopharma AS, P.O. Box 6447, Tromsø Science Park, N-9294 Tromsø, Norway; Department of Chemistry, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
authors.forename: Frederick
authors.initials: F
authors.lastname: Leeson
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, UiT The Arctic University of Norway, N-9037 Tromsø, Norway. Electronic address: richard.engh@uit.no.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Engh
authors.affiliation: Lytix Biopharma AS, P.O. Box 6447, Tromsø Science Park, N-9294 Tromsø, Norway; Department of Chemistry, UiT The Arctic University of Norway, N-9037 Tromsø, Norway. Electronic address: john-sigurd.svendsen@uit.no.
authors.forename: John S
authors.initials: JS
authors.lastname: Svendsen
mesh_terms: D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D049454:Firefly Luciferin / Q000031:analogs & derivatives / Q000737:chemistry*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D000097603:Dyrk Kinases
chemical_list: D051357:Cyclin-Dependent Kinase 2; D049454:Firefly Luciferin; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C495894:CDK2 protein, human
keywords: Crystallography; Drug design; Inhibitor profiling; Luciferin; Protein kinase