Synthesis and target identification of hymenialdisine analogs.
Hymenialdisine (HMD) is a sponge-derived natural product kinase inhibitor with nanomolar activity against CDKs, Mek1, GSK3beta, and CK1 and micromolar activity against Chk1. In order to explore the broader application of the pyrrolo[2,3-c]azepine skeleton of HMD as a general kinase inhibitory scaffold, we searched for additional protein targets using affinity chromatography in conjunction with the synthesis of diverse HMD analogs and profiled HMD against a panel of 60 recombinant enzymes. This effort has led to nanomolar to micromolar inhibitors of 11 new targets including p90RSK, KDR, c-Kit, Fes, MAPK1, PAK2, PDK1, PKCtheta, PKD2, Rsk1, and SGK. The synthesis of HMD analogs has resulted in the identification of compounds with enhanced and/or dramatically altered selectivities relative to HMD (28n) and in molecules with antiproliferative activities 30-fold higher than HMD (28p).
Wan
Yongqin
Y
Genomics Institute of the Novartis Research Foundation, Department of Chemistry, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
Hur
Wooyoung
W
Cho
Charles Y
CY
Liu
Yi
Y
Adrian
Francisco J
FJ
Lozach
Olivier
O
Bach
Stéphane
S
Mayer
Thomas
T
Fabbro
Doriano
D
Meijer
Laurent
L
Gray
Nathanael S
NS
D000595:Amino Acid Sequence; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002846:Chromatography, Affinity; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008969:Molecular Sequence Data; D010770:Phosphotransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001381:Azepines; D004791:Enzyme Inhibitors; D011758:Pyrroles; C107079:hymenialdisine; D010770:Phosphotransferases