Synthesis and target identification of hymenialdisine analogs

Y. Wan , W. Hur , Cho C. Y. , Yehan Liu , Adrian F. J. , O. Lozach (1) , S. Bach , T. Mayer , D. Fabbro , L. Meijer (1) , Gray N. S.

1 MCT - Molécules et cibles thérapeutiques

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).

Mots clés: Amino Acid Sequence Azepines/chemical synthesis/*chemistry/pharmacology Chromatography; Affinity Enzyme Inhibitors/chemical synthesis/*chemistry/pharmacology Molecular Sequence Data Phosphotransferases/*antagonists & inhibitors/metabolism Pyrroles/chemical synthesis/*chemistry/pharmacology Structure-Activity Relationship

Domaines: Biochimie, Biologie Moléculaire

Y. Wan, W. Hur, Cho C. Y., Yehan Liu, Adrian F. J., et al.. Synthesis and target identification of hymenialdisine analogs. Chemistry & biology, 2004, 11, pp.247-259. ⟨hal-00020127⟩