Balanol and Derivatives

The balanols represent a class of potentially therapeutic PKC inhibitors. They are derived from the natural product (-)-balanol, which was first isolated as a metabolite of the fungus Verticillium balanoides at Sphinx Pharmaceuticals (Eli Lilly) (Kulanthaivel et al. 1993) and from a species of Fusar-ium at Nippon Roche (Ohshima et al. 1994). (-)-Balanol inhibits PKC and PKA in the low nanomolar range (Ki=6.4 nM for PKCa, Ki=1.8 nM for PKCbII and Ki=3.9 nM for PKA) and other serine/threonine kinases less potently (e.g. 74 nM for CaMKII and 742 for MAPK); tyrosine kinases are not inhibited (Setyawan et al. 1999). A cocrystal structure of (-)-balanol with PKA was published in 1999 (1BX6) (Hunenberger et al. 1999; Narayana et al. 1999). Balanol derivatives with PKC inhibitory activity have been reported in the literature (Hall et al. 1994; Barbier et al. 1995, 1997; Hu et al. 1995; Koide et al. 1995; Jagdmann et al. 1996; Gustafsson and Brunton 1999; Setyawan et al. 1999; Lampe et al. 2002). New derivatives of balanol have been reported as protein kinase B (PKB/Akt) inhibitors. Cocrystal structures reveal binding modes and are instrumental in optimization of properties, such as selectivity profile against PKA or PKC, etc. (Breitenlechner et al. 2004).

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