eBriefing

Potent Pathways: Structure-Guided Drug Discovery with Protein Kinases

Potent Pathways
Reported by
Megan Stephan

Posted August 12, 2009

Presented By

Biochemical Pharmacology Discussion Group and the American Chemical Society's New York Section

Overview

Protein kinases are the workhorses of cellular regulation, playing a key role in almost every major pathway in eukaryotic cells, including those that control cell division, cell death, cell growth, and programs of differentiation. These proteins play key regulatory roles in plants and bacteria, including many pathogenic microorganisms. Mutations or overexpression of these proteins is implicated in a wide range of diseases, from cancer to diabetes to neurodegenerative diseases.

An April 28, 2009, meeting of the Academy's Chemical Biology Discussion Group featured four researchers who study kinase structure and function and are working to develop these findings into effective therapeutics. Topics discussed included newly identified, potentially druggable targets in protein kinase A; challenges to kinase-directed drug development, including problems related to toxicity, selectivity, efficacy, and patentability; and advances in the relatively new field of fragment-based drug design, in which small chemical fragments are identified by screening as starting points to build larger, drug-like compounds with favorable physicochemical and clinical properties.

Use the tabs above to find a meeting report and multimedia from this event.

 

Web Sites

kinase.com
Explores the functions, evolution and diversity of protein kinases. The Web site includes the extensive KinBase database, as well as papers and supporting material for published work from Sugen (now part of Pfizer) and the Salk Institute.

Protein Kinase Research
European research consortium of over 200 researchers aimed at contributing to future treatments of diseases such as cancer, Alzheimer's, Parkinson's disease, and others.

Protein Kinase Resource
Database of protein kinase structures.

Guide to Protein Crystallography, from Protein Purification to Structure Refinement
Brief primer on the techniques of protein crystallography.

Practical Fragments
Blog intended to promote discussion of fragment-based ligand discovery methods.

Fragment-Based Drug Discovery Literature
Blog that compiles literature and information from meetings about fragment-based ligand discovery.


Articles

Susan Taylor

Kennedy EJ, Yang J, Pillus L, et al. 2009. Identifying critical non-catalytic residues that modulate protein kinase A activity. PLoS ONE 4: e4746.

Kornev AP, Taylor SS, Ten Eyck LF. 2008. A generalized allosteric mechanism for cis-regulated cyclic nucleotide binding domains. PLoS Comput. Biol. 4: e1000056.

Kornev AP, Taylor SS, Ten Eyck LF. 2008. A helix scaffold for the assembly of active protein kinases. Proc. Natl. Acad. Sci. USA 105: 14377-14382.

Taylor SS, Kim C, Cheng CY, et al. 2008. Signaling through cAMP and cAMP-dependent protein kinase: diverse strategies for drug design. Biochim. Biophys. Acta. 1784: 16-26.

Ten Eyck LF, Taylor SS, Kornev AP. 2008. Conserved spatial patterns across the protein kinase family. Biochim. Biophys. Acta. 1784: 238-243.

Yang J, Kennedy EJ, Wu J, et al. 2009. Contribution of non-catalytic core residues to activity and regulation in protein kinase A. J. Biol. Chem. 284: 6241-6248.

Vincent Stoll

Dai Y, Guo Y, Frey RR, et al. 2005. Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors. J. Med. Chem. 48: 6066-6083.

Dai Y, Hartandi K, Ji Z, et al. 2007. Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N′-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor. J. Med. Chem. 50: 1584-1597.

Luo Y, Shoemaker AR, Liu X, et al. 2005. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Mol. Cancer Ther. 4: 977-986.

Zhu GD, Gandhi VB, Gong J, et al. 2007. Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension. J. Med. Chem. 50: 2990-3003.

Zhu GD, Gong J, Claiborne A, et al. 2006. Isoquinoline-pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity. Bioorg. Med. Chem. Lett. 16: 3150-3155.

Zhu GD, Gong J, Gandhi VB, et al. 2007. Design and synthesis of pyridine-pyrazolopyridine-based inhibitors of protein kinase B/Akt. Bioorg. Med. Chem. 15: 2441-2452.

Harren Jhoti

Congreve M, Carr R, Murray C, Jhoti H. 2003. A 'rule of three' for fragment-based lead discovery? Drug Discov. Today 8: 876-877.

Day PJ, Cleasby A, Tickle IJ, et al. 2009. Crystal structure of human CDK4 in complex with a D-type cyclin. Proc. Natl. Acad. Sci. USA 106: 4166-4170.

Gill A, Cleasby A, Jhoti H. 2005. The discovery of novel protein kinase inhibitors by using fragment-based high-throughput X-ray crystallography. Chembiochem. 6: 506-512.

Jhoti H. 2007. Fragment-based drug discovery using rational design. Ernst Schering Found. Symp. Proc. 3: 169-185.

Jhoti H, Cleasby A, Verdonk M, Williams G. 2007. Fragment-based screening using X-ray crystallography and NMR spectroscopy. Curr. Opin. Chem. Biol. 11: 485-493.

Mooij WT, Hartshorn MJ, Tickle IJ, et al. 2006. Automated protein-ligand crystallography for structure-based drug design. ChemMedChem. 1: 827-838.

Stephen Burley

Atwell S, Adams JM, Badger J, et al. 2004. A novel mode of Gleevec binding is revealed by the structure of spleen tyrosine kinase. J. Biol. Chem. 279: 55827-55832.

Burley SK. 2006. Cancer and kinases: reports from the front line. Genome Biol. 7: 314.

O'Hare T, Eide CA, Tyner JW, et al. 2008. SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib. Proc. Natl. Acad. Sci. USA 105: 5507-5512.

Padyana AK, Qiu H, Roll-Mecak A, et al. 2005. Structural basis for autoinhibition and mutational activation of eukaryotic initiation factor 2alpha protein kinase GCN2. J. Biol. Chem. 280: 29289-29299.

Romanowski MJ, Bonanno JB, Burley SK. 2002. Crystal structure of the Streptococcus pneumoniae phosphomevalonate kinase, a member of the GHMP kinase superfamily. Proteins 47: 568-571.

Romanowski MJ, Burley SK. 2002. Crystal structure of the Escherichia coli shikimate kinase I (AroK) that confers sensitivity to mecillinam. Proteins 47: 558-562.

Speakers

Susan Taylor, PhD

University of California, San Diego
e-mail | web site | publications

Susan Serota Taylor is a protein chemist and structural biologist based at the University of California, San Diego, and affiliated with the Howard Hughes Medical Institute. Following a postdoctoral fellowship at the MRC Laboratory of Molecular Biology, Cambridge, England with B.S. Hartley, she joined UCSD as a postdoctoral fellow in 1971, rising from the rank of assistant professor to full professor of chemistry and biochemistry, and professor of pharmacology. Her research led to solving the crystal structure of the first protein kinase in 1991, providing a template for this entire family of essential regulatory enzymes. Her ongoing research is focused on understanding the structure and function of cAMP-dependent protein kinase and the molecular basis for its regulation, localization, and dynamics, which continues to provide an ideal interdisciplinary system for coupling technological advances in computation and biophysics.

Taylor is a member of the National Academy of Science, American Academy of Arts and Sciences, and Institute of Medicine, and is a fellow of the San Diego Super Computer Center. She has published over 300 articles. Her research has been funded by NIH, the American Cancer Society, and NSF.  She is a past president of American Society for Biochemistry and Molecular Biology and served on the board of counselors for the National Cancer Institute, Heart, Lung and Blood Institute, NIDDK, and GM Council for NIH.

Vincent Stoll, PhD

Abbott Laboratories
e-mail | web site | publications

Vincent Stoll earned his PhD in biochemistry from Albert Einstein College of Medicine in 1990, where, with John Blanchard, he studied the use of multiple kinetic isotope effects studies to determine the chemical mechanism of NADH peroxidase. From 1990 to 1992 he conducted postdoctoral research in protein X-ray crystallography at the Max Planck Institute for Medical and Biophysical research in Heidelberg Germany with Prof. Emil Pai, studying the crystal structures and chemical mechanisms of flavoprotein oxidoreductases. He continued his postdoctoral studies with Prof. Pai at the University of Toronto until joining the protein X-ray crystallography group at Abbott in 1997. While at Abbott he has focused on structure-based drug design on antiviral, cancer, and neuroscience targets. He is an inventor on six issued patents and has more than 30 publications while at Abbott. Vincent is currently the project leader of X-ray crystallography, molecular modeling, and optical spectroscopy at Abbott.

Harren Jhoti, PhD

Astex Therapeutics
e-mail | web site | publications

Harren Jhoti is Founder & Chief Executive of Astex Therapeutics, a UK-based biotechnology company with around 75 employees that has raised over £70M venture capital. Astex has pioneered fragment-based drug discovery and generated three novel drug molecules that are in clinical development. His publications include papers in leading journals such as Nature and Science and he has also featured in Time magazine after being named by the World Economic Forum as a Technology Pioneer. He was also recently named by the Royal Society of Chemistry as 'Chemistry World Entrepreneur of the Year' for 2007. Before setting-up Astex in 1999, he was previously head of structural biology and bioinformatics at GlaxoWellcome in the UK (1991–1999).

Stephen K. Burley, DPhil, MD

SGX Pharmaceuticals
e-mail | publications

Stephen Burley is a Distinguished Lilly Scholar at the Eli Lilly Center for Excellence in Biotechnology at San Diego, California. Burley joined Lilly in 2008 following its acquisition of SGX Pharmaceuticals, Inc., where he served as senior vice president and chief scientific officer. Prior to 2002, Burley was the Richard M. and Isabel P. Furlaud Professor at the Rockefeller University and a member of the Howard Hughes Medical Institute. Burley received his undergraduate training in physics at the University of Western Ontario. As a Rhodes Scholar, he returned to his native England, where he completed a DPhil in structural biology in 1983. Thereafter, he received MD training at Harvard Medical School and clinical training in internal medicine at the Brigham and Women's Hospital in Boston. Burley's research interests are in structure-guided and fragment-based drug discovery and high-throughput structural studies of globular and integral membrane proteins.


Megan Stephan

Megan Stephan studied transporters and ion channels at Yale University for nearly two decades before giving up the pipettor for the pen. She specializes in covering research at the interface between biology, chemistry and physics. Her work has appeared in The Scientist and Yale Medicine. Stephan holds a PhD in biology from Boston University.