Vol. 56, Issue 2, 370-376, August 1999

Inhibition of Protein Kinases by Balanol: Specificity within the Serine/Threonine Protein Kinase Subfamily

Juliana Setyawan, Kazunori Koide, Thomas C. Diller, Mark E. Bunnage, Susan S. Taylor, K. C. Nicolaou, and Laurence L. Brunton

Departments of Pharmacology and Medicine (J.S., L.L.B.) and Chemistry and Biochemistry (K.K., T.C.D., M.E.B., S.S.T., K.C.N.), University of California at San Diego, La Jolla, California; and Department of Chemistry, The Scripps Research Institute, La Jolla, California (M.E.B., K.C.N.)

Balanol is a potent inhibitor of cyclic AMP-dependent protein kinase and protein kinase C, acting competitively with ATP with an affinity 3000 times that of ATP. We tested the capacity of balanol to inhibit representative serine- and threonine-specific protein kinases from the protein kinase subfamily that shares a common conserved catalytic core with cyclic AMP-dependent protein kinase. Balanol's pattern of interactions indicates considerable diversity of the ATP/balanol-binding sites of protein kinases within familial groups and even among isoforms of the same kinase. We propose that balanol is a protean structure that may be modified to produce selective, high-affinity inhibitors and probes of the ATP-binding sites of serine/threonine protein kinases.