Monday, June 21
7:30 am Registration and Morning Coffee
8:30 Chairperson’s Remarks
Thomas Vondriska, Ph.D., Assistant Professor, Anesthesiology, Medicine & Physiology, UCLA
8:35 Kinase Inhibitors as Potential Therapeutics for Cerebral Ischemia
Gregory Cuny, Ph.D., Assistant Professor, Neurology, Brigham & Women’s Hospital and Harvard Medical School
The presentation will describe various kinases implicated in the patho-physiology of cerebral ischemia and both the opportunities and challenges for developing kinase inhibitors to treat this common and often devastating condition. Two new strategies utilizing RIP1 and EphB3 kinase inhibitors as potential therapeutics for cerebral ischemia will also be highlighted.
9:05 Addressing Major Challenges in Development of Small Molecule Drugs for CNS Indications
D. Martin Watterson, Ph.D., J.G. Searle Professor & Co-Director, Center for Drug Discovery & Chemical Biology, Northwestern University
Inadequate blood brain barrier penetrance of small molecule dugs is a major challenge in CNS drug discovery. The overrepresentation of CYP2D6 substrates among CNS drugs increases the risk for individual variance and adverse pharmacology events. Recently described parsed databases of small molecules with in vivo evidence of CNS tissue uptake and kinetically validated CYP2D6 substrate status has allowed statistical analyses of small molecule trends that correlate with CNS penetrance and avoidance of CYP2D6 substrate status. Such probability bias can be used as a component of pharmacology-driven medicinal chemistry campaigns to generate novel potential therapeutic candidates for CNS disorders.
9:35 Dual Jak3/Syk Inhibitors: A Novel Approach to the Treatment of Autoimmune Disease
Xavi Bartroli, Ph.D., Director, Drug Discovery, Palau Pharma
We have discovered a series of highly potent dual inhibitors of Jak3 and Syk, showing excellent efficacies in animal models of RA, EAE, GVHD, organ transplant, asthma and psoriasis. Compounds are presently entering pre-clinical development. Targeting both Jak and Syk in a single compound represents a wider way to modify disease by intervention at more than one point. On one hand, inhibition of Jak3 modulates γc cytokine downstream signalling, a key pathway causing autoimmune disease, and on the other, inhibition of Syk controls B cell antibody response to antigen through BCR as well as blocks Fc-receptor signalling of immunoglobins.
10:05 Networking Coffee Break, Poster and Exhibit Viewing
10:45 How the Proteome Acts on the Genome, Causing the Heart to Fail: New Approaches for Therapeutic Intervention
Thomas Vondriska, Ph.D., Assistant Professor, Anesthesiology, Medicine & Physiology, UCLA
Heart failure is an incurable disease that affects millions of Americans. New approaches such as next generation sequencing and proteomics have revealed new signaling pathways that modulate this disease phenotype. Importantly, they suggest new therapeutic targets, including kinases, phosphatases and other signaling proteins.
11:15 Cardiovascular Effects of the Novel Rho-Kinase Inhibitor SARr407899
Matthias Loehn, M.D., R&D TD Cardiovascular FFM, sanofi-aventis Deutschland GmbH
Recent advances in basic and clinical research have identified Rho-kinase (ROCK) as an important target potentially implicated in a variety of cardiovascular diseases. Increased ROCK activity is associated with vasoconstriction and elevated blood pressure. We identified a novel inhibitor of ROCK (SAR407899) and characterized its effects in biochemical, cellular, tissue-based, and in vivo assays. SAR407899 is an ATP-competitive ROCK inhibitor and equipotent against human and rat-derived ROCK and is highly selective in panel of 117 receptor and enzyme targets. In vivo, SAR407899 lowered blood pressure and showed end-organ protective effects in a variety of rodent models of arterial hypertension.
11:45 Talk Title to be Announced
Michael J. Eck, Ph.D., Professor, Biological Chemistry & Molecular Pharmacology, Dana Farber Cancer Institute
12:15 pm Luncheon Presentation
The Importance of Membrane Context in Assaying Membrane Associated Kinases: A Case Study of AKT Activation
Scott Gridley, Ph.D., Director, Product Development, Metabolic Diseases, Blue Sky Biotech, Inc.
1:40 Chairperson’s Remarks
1:45 FEATURED PRESENTATION
Discovery of Novel Multiplex PI3 Kinase Inhibitors for the Treatment of Cancer
Dapeng Qian, M.D., Ph.D., Senior Director, Drug Discovery, Progenics Pharmaceuticals, Inc.
The simultaneous dysregulation of both PI3K and Ras pathways is characteristic of some of the most aggressive forms of human cancer, (e.g. Ras mutated tumors). It has been demonstrated in preclinical studies that effective treatment of Ras-mutated tumors requires blockade of both pathways. Therefore, the ability to achieve this outcome with a single agent holds great clinical promise. Approaches to the discovery of novel multiplex PI3K inhibitors that simultaneously target both pathways will be discussed.
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2:25 Developing a Novel, Selective, and Orally Bioavailable Inhibitor of the Trk Kinase Pathway
Charles Omer, Ph.D., Project Director, Cancer Biosciences, AstraZeneca
Sponsored by
2:55 Phosphoproteomics: New Strategies for the Mode-of-Action Analysis of Targeted Drugs and for the Identification of Biomarkers for Personalized Cancer TherapyJutta Fritz, Ph.D., Head of Technology & Business Development, KINAXO Biotechnologies GmbHKINAXO’s phosphoproteomics platform PhosphoScout enables identification of regulated protein phosphorylation sites in response to therapeutic antibody or kinase inhibitor treatment. Using state-of-the-art quantitative mass spectrometry, up to 15,000 phosphorylation sites can be monitored in a single experiment thereby facilitating the analysis of the phosphoproteome in patient samples and animal models on a global scale. This makes PhosphoScout an emerging technology for drug mode of action analysis and the stratification of cancer patients receiving targeted therapies.
3:25 Networking Refreshment Break, Poster and Exhibit Viewing
4:10 Mitotic Spindle Kinase Inhibitors to Target Aneuploid Cancer Cells
Jürgen Moll, Ph.D., Director, Department of Cell Biology and Oncology, Nerviano Medical Sciences Srl.
Aneuploidy is a hallmark of most cancer types. The consequences of aneuploidy on cellular functions and ideas to target specifically aneuploid cancer cells will be discussed. One approach is to interfere with mitotic spindle assembly checkpoint components to specifically kill aneuploid cancer cells. A case study of NMS-P715, a highly selective ATP-competitive small molecule MPS-1 kinase inhibitor, will be presented.
4:40 CAL-101 a PI3K Delta Isoform Selective Inhibitor has Provided a Novel Therapeutic Strategy for the Treatment of B Cell Malignancies
Neill Giese, Ph.D., CSO, Calistoga Pharmaceuticals, Inc.
CAL-101 inhibition of PI3K delta in malignant B cells blocks constitutive pathway activation and signaling mediated by proliferation and survival factors in the tumor microenviornment leading to apoptotic cell death. Preclinical efficacy has been demonstrated in multiple tumor types including nonhodgkins lymphoma and chronic lymphocytic leukemia. These studies have provided the initial proof of concept for the ongoing clinical trials.
Sponsored by
5:10 4SC-203: A Novel Multi-Protein Kinase Inhibitor for the Treatment of Acute Myeloid LeukaemiaMichael Kubbutat, Ph.D., Head R&D, ProQinase GmbHAcute myeloid leukaemia is one of the most common leukaemias in humans, with a high relapse rate within two years after initial chemotherapy treatment leading to a high mortality of the patients.In a joint effort, 4SC AG, Munich, Germany, and ProQinase GmbH, Freiburg, Germany developed 4SC-203, a novel multi-protein kinase inhibitor for the treatment of AML. 4SC-203 inhibits FLT3 wt, and tumor relevant mutants with high potency in vitro and in cells. In addition other targets also known to be relevant for the growth of AML are inhibited such as VEGF-R2 indicating that the compound can attack AML via different pathways. In vivo studies using MV4-11 xenograft models show excellent tumor growth inhibition after iv application of the drugs, and preclinical characterisation revealed that the drug is well tolerated leading to recent initiation of a clinical phase 1 study.
5:30 Happy Hour in Exhibit Hall
6:30 End of Day One