Fungal Metabolites as Potent Protein Kinase Inhibitors: Identification of a Novel Metabolite and Novel Activities of Known Metabolites

A novel undecylresorcinol dimer ( 1 ) was isolated from Coleophoma sp. andinhibited cFMS receptor tyrosine kinase (IC 50 of 0.4 µM), with greater than 10-foldselectivity versus nine other protein kinases. The known fungal metabolites balanoland altenusin inhibited cFMS kinase and pp60c-Src kinase, respectively, even more potently and selectively.Altenusin inhibited pp60c-Src with an IC 50 of 20 nM and a selectivity of at least 400-fold versus nine otherprotein kinases. Balanol inhibited cFMS receptor kinase with an IC 50 of 1 nM and selectivities of 14-75-foldversus pp60c-Src and VEGF receptor kinases and greater than 10,000-fold versus seven other kinases. Keywords: fungal metabolite, protein kinase inhibitor, cFMS receptor tyrosine kinase, pp60c-Src kinase, balanol, altenusin,alternariol. INTRODUCTION Natural products are a rich source for inhibitors of proteinkinases (ex, erbstatin, coumarins, staurosporines,lavendustin, etc, [1]). Although many of these compoundsare polyhydroxylated aromatics and not considered goodchemical templates for pharmaceutical development, there areindeed several natural products (or derivatives) that arecurrently in clinical trials (ex, flavopiridol, bryostatin-1,PKC412, UCN 01, [2]). In addition, natural products areoften used as tool compounds because of their potency orselectivity. For example, wortmannin is routinely used as apotent and selective inhibitor of phosphatidylinositol-3-kinase both