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Marine Derived Hamacanthins as Lead for the Development of Novel PDGFRβ Protein Kinase Inhibitors
Institute of Pharmacy, University of Kiel, Gutenbergstraße 76, Kiel D-24118, Germany
European ScreeningPort GmbH, Schnackenburgallee 114, Hamburg D-22525, Germany
ProQinase GmbH, Breisacherstraße 117, Freiburg D-79106, Germany
* Author to whom correspondence should be addressed.
Received: 7 June 2013; in revised form: 1 August 2013 / Accepted: 8 August 2013 / Published: 26 August 2013
Abstract: In this study, we report on pyrazin-2(1H)-ones as lead for the development of potent adenosine triphosphate (ATP) competitive protein kinase inhibitors with implications as anti-cancer drugs. Initially, we identified the pyrazin-2(1H)-one scaffold from hamacanthins (deep sea marine sponge alkaloids) by Molecular Modeling studies as core binding motif in the ATP pocket of receptor tyrosine kinases (RTK), which are validated drug targets for the treatment of various neoplastic diseases. Structure-based design studies on a human RTK member PDGFR (platelet-derived growth factor receptor) suggested a straight forward lead optimization strategy. Accordingly, we focused on a Medicinal Chemistry project to develop pyrazin-2(1H)-ones as optimized PDGFR binders. In order to reveal Structure-Activity-Relationships (SAR), we established a flexible synthetic route via microwave mediated ring closure to asymmetric 3,5-substituted pyrazin-2(1H)-ones and produced a set of novel compounds. Herein, we identified highly potent PDGFR binders with IC50 values in an enzymatic assay below µM range, and possessing significant activity against PDGFR dependent cancer cells. Thus, marine hamacanthin-derived pyrazin-2(1H)-ones showing interesting properties as lead for their further development towards potent PDGFR-inhibitors.
Keywords: marine sponge derived hamacanthins; pyrazin-2(1H)-ones; receptor tyrosine kinases; PDGFR inhibitors; anti-cancer activity
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MDPI and ACS Style
Pinchuk, B.; Johannes, E.; Gul, S.; Schlosser, J.; Schaechtele, C.; Totzke, F.; Peifer, C. Marine Derived Hamacanthins as Lead for the Development of Novel PDGFRβ Protein Kinase Inhibitors. Mar. Drugs 2013, 11, 3209-3223.
Pinchuk B, Johannes E, Gul S, Schlosser J, Schaechtele C, Totzke F, Peifer C. Marine Derived Hamacanthins as Lead for the Development of Novel PDGFRβ Protein Kinase Inhibitors. Marine Drugs. 2013; 11(9):3209-3223.
Pinchuk, Boris; Johannes, Eugen; Gul, Sheraz; Schlosser, Joachim; Schaechtele, Christoph; Totzke, Frank; Peifer, Christian. 2013. "Marine Derived Hamacanthins as Lead for the Development of Novel PDGFRβ Protein Kinase Inhibitors." Mar. Drugs 11, no. 9: 3209-3223.