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Synthesis and Target Identification of Hymenialdisine Analogs

2004; Elsevier BV; Volume: 11; Issue: 2 Linguagem: Inglês

10.1016/j.chembiol.2004.01.015

1879-1301

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

Chemical Synthesis and Analysis

Hymenialdisine (HMD) is a sponge-derived natural product kinase inhibitor with nanomolar activity against CDKs, Mek1, GSK3β, 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, PKCθ, 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).