Chemistry & Biology 2004-02-01

Synthesis and target identification of hymenialdisine analogs.

Yongqin Wan, Wooyoung Hur, Charles Y Cho, Yi Liu, Francisco J Adrian, Olivier Lozach, Stéphane Bach, Thomas Mayer, Doriano Fabbro, Laurent Meijer, Nathanael S Gray

Index: Chem. Biol. 11(2) , 247-59, (2004)

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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).