Monday, June 4
8:00 - 9:00 am Pre-Conference Short Course Registration and Morning Coffee
11:00 am Main Conference Registration
1:30 pm Chairperson’s Remarks
1:40 Multiple Strategies for Overcoming Kinase Inhibitor Resistance
Nathanael S. Gray, Ph.D., Professor, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
2:10 Resistance of Akt Kinases to Dephosphorylation through ATP-Dependent Conformational Plasticity
Roger S. Armen, Ph.D., Assistant Professor of Medicinal Chemistry, Department of Pharmaceutical Sciences, Thomas Jefferson University, School of Pharmacy
Phosphorylation of a threonine residue (T308 in Akt1) in the activation loop of Akt kinases is a prerequisite for deregulated Akt activity frequently observed in cancer. We describe that targeting Akt kinase to the cell membrane markedly reduced sensitivity of phosphorylated Akt to dephosphorylation, and that this effect was amplified by occupancy of the ATP binding pocket by either ATP or ATP competitive inhibitors. We describe a mechanism that provides an explanation for the “paradoxical” Akt hyperphosphorylation induced by certain ATP-competitive inhibitors.
2:40 A Broad Profiling Screen in Support of a Chemogenomic Map for Drug Discovery and Kinase SignalingKevin J. Harvey, Ph.D. Sr. Manager R&D, EMD MilliporeTo better understand the nature of structure and activity across the kinome, and how they relate to off-target effects, we screened a well-defined collection of kinase inhibitors using “gold standard” radiometric assays for inhibitory activity toward 234 human kinases representing all branches of the kinome tree. We screened 158 small molecules initially identified in the literature as potent inhibitors of important signaling kinase targets and provide a framework for assessing their selectivity and potency.
3:10 Refreshment Break in the Exhibit Hall with Poster Viewing
3:40 Aptamers: A New Class of Tyrosine Kinase Inhibitors
Said Ismail, Ph.D., Associate Professor, Molecular Biology, Department of Biochemistry, Medical School, University of Jordan
Aptamers are short single stranded nucleic acids developed by the SELEX method to specifically target various molecules including proteins. Our lab has developed a large number of aptamers against several tyrosine kinase (TK) targets involved in different malignancies. Our aptamers have shown a great potential to specifically bind and inhibit their TK targets, which offers a great promise for their therpaeutic uses.
4:10 Kinase Inhibitor Profiling using a Luminescent ADP Detection Platform with Complete Profiling SystemsHicham Zegzouti, Ph.D., Senior Research Scientist, R&D, Promega CorporationThe ADP-GloTMkinase assay is a universal, sensitive and robust platform that addresses all the needs of kinase screening, mode of action (MOA) studies and inhibitor profiling. Thisluminescent platformhas been validated for more than one-hundred kinases and is now optimized for use with a large panel of complete Kinase Enzyme Systems (KES) that span the different families of the human kinome. Here we demonstrate the profiling of several kinase inhibitors using standardized kinase strips. We show that using this new platform we can easily generate inhibitory profiles of small or large kinase panels of a single kinase subfamily or different subfamilies of the kinome. The fact that the ADP-Gloplatform offers so many positive attributes makes it an ideal assay not only for primary and secondary screening but also for profiling compounds in a cost-effective manner using one single platform.
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4:40 Development and Activity of Inhibitors of the Atypical Mitotic Kinase Haspin
Jonathan Higgins, Ph.D., Assistant Professor, Medicine, Brigham & Women’s Hospital, Harvard Medical School
Our work has defined the atypical kinase Haspin as a histone H3 kinase that is required for regulating Aurora B activity and chromosomes segregation in mitosis, and has suggested that Haspin is a suitable target for the development of anti-mitotic cancer therapies. Using high throughput screening, followed by medicinal chemistry guided by structural analysis and molecular modeling, we have identified and developed small molecule inhibitors of Haspin, and have also defined the mechanism of their anti-mitotic activity. These results and studies by others suggest that such compounds might have anti-tumor activity both as single agents and in combination with Aurora inhibitors.
5:10 Welcome Reception in the Exhibit Hall with Poster Viewing
6:45 Close of Day One