“Inhibitors of PKC-beta and GSK-3beta: A Tale of Two Kinases”
Bruce Maryanoff,
Distinguished Research Fellow
Johnson & Johnson
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Abstract: Protein kinase C (PKC) enzymes regulate vascular tone, vascular permeability, and cell proliferation, and are involved in cardiovascular disease, cancer, ischemia, inflammation, and CNS disorders. Since PKC-b is induced in response to hyperglycemia in cardiac, aortic, renal, and retinal tissues, its inhibition has therapeutic potential for treating diabetic complications. Glycogen synthase kinase-3 (GSK-3) plays an important role in glucose homeostasis, CNS function, and cancer. Inhibition of GSK-3b-dependent phosphorylation should activate insulin-dependent glycogen synthesis, thereby affording a novel mode of treating type II diabetes. This talk will describe novel maleimide-based compounds with interesting selectivity profiles between PKC-b and GSK-3b, as well as a series of macrocyclic dual inhibitors. Also, a [2+2+2] cyclo-cotrimerization approach to “multiheterophanes” that selectively inhibit GSK-3b will be presented. Several challenges encountered in the preclinical evaluation of key lead compounds will be discussed.
Presenter Biography: Bruce E. Maryanoff was born in Philadelphia, Pennsylvania, in 1947. He earned his B.S. (1969) and Ph.D. (1972) degrees from Drexel University, the latter under the direction of Prof. Robert O. Hutchins. After conducting postdoctoral studies at Princeton University with Prof. Kurt M. Mislow, he joined McNeil Laboratories, a Johnson & Johnson company, in 1974. He advanced to Distinguished Research Fellow, the highest scientific position, and also served as a Team Leader for the past 15 years. Dr. Maryanoff has worked on drugs for central nervous system and cardiovascular disorders, and discovered TOPAMAX® topiramate, which is useful for the treatment of epilepsy and migraine. He has published 260 scientific papers and is an inventor on 95 U.S. patents (issued or pending). He has received two ACS national awards, Heroes of Chemistry Award-2000 and Award in Industrial Chemistry-2003, and the 2009 Edward E. Smissman Award from the ACS Division of Medicinal Chemistry. He was inducted into the ACS Division of Medicinal Chemistry Hall of Fame (2008), is a Fellow of the American Association for the Advancement of Science (AAAS), and is a Fellow of the Royal Society of Chemistry.
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