Luciferin and derivatives as a DYRK selective scaffold for the design of protein kinase inhibitors

Ulli Rothweiler; Jonas Eriksson; Wenche Stensen; Frederick Leeson; Richard A Engh; John S Svendsen

doi:10.1016/j.ejmech.2015.02.035

Luciferin and derivatives as a DYRK selective scaffold for the design of protein kinase inhibitors

Eur J Med Chem. 2015 Apr 13:94:140-8. doi: 10.1016/j.ejmech.2015.02.035. Epub 2015 Feb 25.

Authors

Ulli Rothweiler¹, Jonas Eriksson², Wenche Stensen³, Frederick Leeson³, Richard A Engh⁴, John S Svendsen⁵

Affiliations

¹ The Norwegian Structural Biology Centre, Department of Chemistry, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
² Lytix Biopharma AS, P.O. Box 6447, Tromsø Science Park, N-9294 Tromsø, Norway.
³ 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.
⁴ The Norwegian Structural Biology Centre, Department of Chemistry, UiT The Arctic University of Norway, N-9037 Tromsø, Norway. Electronic address: richard.engh@uit.no.
⁵ 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.

PMID: 25768698
DOI: 10.1016/j.ejmech.2015.02.035

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.

Keywords: Crystallography; Drug design; Inhibitor profiling; Luciferin; Protein kinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Crystallography, X-Ray
Cyclin-Dependent Kinase 2 / antagonists & inhibitors
Cyclin-Dependent Kinase 2 / chemistry
Drug Design
Drug Evaluation, Preclinical / methods*
Dyrk Kinases
Firefly Luciferin / analogs & derivatives
Firefly Luciferin / chemistry*
Humans
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / chemistry
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Firefly Luciferin
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases
CDK2 protein, human
Cyclin-Dependent Kinase 2