Wan, Yongqin, Hur, Wooyoung, Cho, Charles, Liu, Yi, Adrian, Francisco, Lozach, Olivier, Bach, Stephane, Mayer, Thomas, Fabbro, Doriano, Meijer, Laurent and Gray, Nathanael (2004) Synthesis and target identification of hymenialdisine analogs. Chemistry & Biology, 11 (2). pp. 247-259. ISSN 1074-5521

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).

Item Type:	Article
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Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez...
Date Deposited:	14 Dec 2009 14:02
Last Modified:	31 Jan 2013 01:21
URI:	https://oak.novartis.com/id/eprint/277