Marine derived hamacanthins as lead for the development of novel PDGFRβ protein kinase inhibitors.
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.
Institute of Pharmacy, University of Kiel, Gutenbergstraße 76, Kiel D-24118, Germany.
Boris
B
Pinchuk
Eugen
E
Johannes
Sheraz
S
Gul
Joachim
J
Schlosser
Christoph
C
Schaechtele
Frank
F
Totzke
Christian
C
Peifer
D000255:Adenosine Triphosphate / Q000378:metabolism; D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D061986:MCF-7 Cells; D011161:Porifera / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta