title: Synthesis and target identification of hymenialdisine analogs.
abstract: 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).
authors.affiliation: Genomics Institute of the Novartis Research Foundation, Department of Chemistry, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Yongqin
authors.initials: Y
authors.lastname: Wan
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Hur
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Cho
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Adrian
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bach
authors.forename: Thomas
authors.initials: T
authors.lastname: Mayer
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: 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
chemical_list: D001381:Azepines; D004791:Enzyme Inhibitors; D011758:Pyrroles; C107079:hymenialdisine; D010770:Phosphotransferases