2nd Protein Kinases in Drug Discovery (PK 2007)

Venue: Boston

Location: Boston, Massachusetts, United States

Event Date/Time: May 31, 2007 End Date/Time: Jun 01, 2007
Registration Date: May 31, 2007
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7:00 Registration & Breakfast

7:50 Chairperson's Opening Remarks
Paul Jackson, Ph.D., Team Leader, CNS Research, Johnson & Johnson

The Pfizer Kinase Center of Emphasis: Unleashing the Kinome for Drug Discovery

Jessie English, Ph.D., Director, Kinase Center of Emphasis, Pfizer, Inc.

Session I: New Technologies for Identifying Kinase Targets and Inhibitors

9:00 Structure-Based Drug Design for Kinase Inhibitors
Jamal Saeh, Ph.D., Computational Chemist, Cancer Chemistry Department, AstraZeneca

9:30 Profiling Protein Kinases with Activity-Based Probes
Sanjay Khandekar, Ph.D., M.B.A., Global Commercial Strategy, Oncology, GlaxoSmithKline

10:00 Refreshment Break

10:30 NMR-guided Design of Protein Kinase Inhibitors
Mark McCoy, Ph.D., Research Fellow, Schering-Plough Research Institute
We use NMR methods to search for low molecular weight hits that can either be assembled into leads using a fragment-based approach or serve as scaffolds for chemical exploration that is guided by SAR from NMR data. Low MW compounds typically have low affinities. While the reliable evaluation of weak hits poses a formidable challenge for bioassay-based screening, NMR methods are well-suited to provide accurate data on low affinity binders. Ligand-detected NMR methods such as ATP-STD NMR are used to rapidly and accurately determine uM-mM Ki’s of ATP-competitive inhibitors. Binding of non-ATP competitive compounds can also be detected. Both active and inactive kinases can be screened. Concepts such as ligand binding efficiency are used to compare the affinities of scaffolds with different MW and to monitor the effectiveness of substitutions to the scaffold. The high reliability NMR data for weak hits can also impact the evaluation of existing kinase screening libraries. In one example, SAR from NMR data was used identify the correct binding mode of a series of low affinity screening hits that, through structure-guided optimization, ultimately lead to a potent series of Akt inhibitors.
Speaker Bio:
Mark McCoy received his Ph.D. in Chemistry from Princeton University in 1988. He carried out postdoctoral NMR research in the lab of Prof. Richard Ernst at ETH-Zürich and in the protein NMR group of Luicano Mueller at Bristol Myers-Squibb. He has held senior scientist positions in the structural biology groups at Sterling-Winthrop and the Wistar Institute. He is currently a Research Fellow at the Schering-Plough Research Institute where he applies NMR screening and structural studies to anticancer and antiviral targets.

a Classifying Protein Kinase Structures Guides use of Ligand-selectivity Profiles to Predict Inactive Conformations
Brian Hare, Ph.D., Research Fellow, Computational & Systems Biology, Vertex Pharmaceuticals
Numerous X-ray structures of protein kinases reveal that the ATP sites adopt distinct conformations, despite having very similar primary sequences and global folds. We elucidate kinase conformations by clustering 3D protein kinase structures based on ATP site conformation, revealing three discrete clusters. One cluster includes kinases in catalytically-active conformations. Each of the other clusters contains a distinct inactive conformation. Typically, kinases adopt at most one of the inactive conformations in available X-ray structures, implying that one of the conformations is preferred for many kinases. Furthermore, we show that ligand selectivity profiles guide kinase classification. We report the X-ray structure of the lck / imatinib (Gleevec) complex, confirming that the conformation adopted by lck is distinct from other structurally-characterized src-family kinases. Targeting this lck conformation may be a novel route for designing inhibitors selective for lck among src-family kinases.
Speaker Bio:
Brian Hare received his Ph.D. degree in Molecular Biophysics and Biochemistry from Yale University in 1994 and conducted postdoctoral work in protein NMR in Gerhard Wagner’s laboratory at Harvard Medical School. He is currently a Research Fellow in computational and systems biology at Vertex Pharmaceuticals. He is applying computational analyses to understand complex biological systems, leverage 3D structural information to guide medicinal chemistry and discover biomarkers.

11:30 TBA
Carsten Hopf Group Leader Target Discovery Cellzome AG


Novel fluorescent Technologies for Kinase Assays in Lead Generation and Optimization: Comparisons of Protease-Catalyzed FRET (Z-Lytetm), Ligand-competitive FP (PolarScreentm) and ADP-Competitive FP (Transcreenertm) Relative to Traditional Radiometric Filter Binding
Robert Campbell, Ph.D., Senior Research Advisor, Eli Lilly & Company

12:30 Lunch

Session II: Kinase Targets and Inhibitors in Oncology

A Discovery of the Multi- Kinase Inhibitor Dasatinib (SPRYCEL®) for the Treatment of Philadelphia Chromosome Positive Leukemias
Jagabandhu Das, Ph.D., Research Fellow, Drug Discovery Chemistry, Bristol Myers Squibb
We have recently identified substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)-thiazole-5-carboxamides as potent multi- kinase inhibitors with excellent antiproliferative activity against solid tumor and hematological cell lines. Moreover, the orally bioavailable, 2-aminopyrimidinyl derivative dasatinib (SPRYCEL®) retains activity in several clinically relevant imatinib-resistant cell lines and provides complete tumor regressions at multiple dose levels in wild-type and imatinib-resistant in vivo tumor models of chronic myelogenous leukemia (CML). Consistent with these preclinical findings, dasatinib demonstrated significant hematologic and cytogenetic response rates in CML and Ph+ ALL patients with resistance or intolerance to imatinib. Crystallographic analysis of dasatinib bound to the Abl kinase domain reveals that dasatinib binds to the activated form of the kinase. The crystal structure also provides mechanistic rationale for the ability of dasatinib to overcome all known imatinib-resistant Bcr-Abl mutants, except for the T315I variant. The structure-activity relationship sudies, preclinical pharmacology and structural biology supporting the selection of dasatinib for clinical development will be discussed.
Speaker Bio:
Received Ph. D. degree in chemistry from the University of New Brunswick, Fredericton, NB, Canada in 1978. Joined Squibb Institute for Medical Research as a research investigator in 1982 after postdoctoral research in the laboratory of Prof. E. J. Corey at Harvard University. At present is a research fellow in Drug Discovery Chemistry at Bristol-Myers Squibb Pharmaceutical Research Institute. Extensive research experience in organic synthesis , and medicinal chemistry with concentration in immunology, oncology, and cardiovascular diseases. Holder of 57 issued U. S. patents and 45 publications. Listed as who’s who in American Men and Women of Science, and Marquis’ who’s who in America. Co-discoverer of the multi-kinase inhibitor dasatinib (SPRYCEL®)which is currently approved for the treatment of chronic myeloid leukemia (CML), and Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) in patients with resistance to or intolerant of prior therapy including imatinib.

Development of One-Armed 5D5 (OA5D5), a Humanized, Monovalent, Monoclonal Antibody against c-Met with Activity against HGF-driven c-Met Activation In Vitro and In Vivo
Mark Merchant, Ph.D., Scientist, Department of Translational Oncology, Genentech, Inc.
The RTK c-Met and its ligand, HGF are correlated with poor prognosis in numerous human cancers. One-armed 5D5 (OA5D5) is a humanized, monovalent, antagonistic anti-c-Met antibody, derived from the agonistic monoclonal antibody (mAb) 5D5 that we have developed to target this pathway. The 5D5 mAb blocks HGF from binding to c-Met, however dimerizes and activates c-Met. 5D5 Fab fragments also block HGF binding, however act as antagonists. As it is difficult to achieve therapeutic levels of Fab fragments in vivo, a monovalent Fab/Fc form of 5D5 (OA5D5) was engineered. The novel design of OA5D5 utilizes knobs-into-holes mutations in the Fc region that enable assembly of a functional monovalent antibody when expressed in E. coli. OA5D5 binds to c-Met with high affinity and prevents HGF binding and subsequent downstream activity. In mice, OA5D5 has a half-life of 3-6 days. OA5D5 has significant anti-tumor efficacy in human glioblastoma (U87 MG) and pancreatic ductal carcinoma (KP4) subcutaneous models where HGF is produced as an autocrine growth factor. Anti-tumor efficacy is observed with single OA5D5 doses of 7.5 mg/kg and above. Together, these results show that OA5D5 is a potent, anti-c-Met monovalent antibody with promise as a therapeutic antibody in human cancer.

2:30 Clinical Antitumor Activity of HKI-272, an Irreversible Pan-ErbB Kinase Inhibitor
Sridhar Rabindran, Ph.D., Associate Director, Oncology Research, Wyeth Research
Speaker Bio:
Dr Rabindran is Associate Director of Oncology Research at Wyeth Research in Pearl River, NY. He is the head of the Cell Cycle Checkpoints/Genomic Instability group, and is currently involved identifying and validating novel anticancer drug targets in this area, carrying out anticancer drug screening and overseeing early preclinical drug development. Dr Rabindran received his B.Sc. from St Xavier’s College of the University of Bombay, Bombay, India, and his Ph.D. from the University of South Carolina, Columbia, SC. He completed his post-doctoral training at the National Cancer Institute of the National Institutes of Health in Bethesda, MD, where he studied the structure and function of HSF1, a transcription factor regulating human heat shock gene expression. Dr Rabindran then joined the Medical Research Division of the American Cyanamid Company, in Pearl River, NY, as a Senior Research Scientist to study multiple drug resistance in human cancers. Following the acquisition of American Cyanamid by American Home Products Corporation (now Wyeth), he established and directed the Cell Cycle Checkpoints program.

3:00 TBA
Bert Klebl, Ph.D., Senior Director, Discovery Biology, GPC Biotech AG

3:30 Refreshment Break

4:00 The Discovery of Chk1 Inhibitors and Biomarkers
Hai-Ying Zhang, Ph.D., Department of Cancer Research, Abbott Laboratories


Kinase Inhibition in Acute vs. Chronic Disorders

Paul Jackson, Ph.D., Team Leader, CNS Research, Johnson & Johnson
Jessie English Ph.D. Director, Kinase Center of Emphasis Pfizer, Inc.
Andrew West, Ph.D., Instructor, Department of Neurology, Johns Hopkins University
Maria Webb, Ph.D., VP Preclinical Research, Biological & Pharmacological Sciences, Pharmacopeia
Sridhar Rabindran, Ph.D., Associate Director, Oncology Research, Wyeth Research

Critical Discussion Points:

Is Inhibition of Kinases Really a Viable Path Forward for the Treatment of Chronic Disorders
Selectivity - What are the Advantages and Disadvantages for Treating Different Disorders
What are the Clinical Issues and How Will They be Addressed

5:30 Networking Reception and Poster Session

Top of Page

June 1, 2007

7:30 Registration & Breakfast
Session III: Kinase Targets and Inhibitors in CNS Disorders

8:00 Leucine-Rich Repeat Kinase 2 as a Therapeutic Target for Parkinson's Disease
Frank Gillardon, Ph.D., Lab Head, CNS Research, Boehringer Ingelheim Pharma GmbH Co & KG
Autosomal-dominant mutations in the human Leucine-Rich Repeat Kinase 2 (LRRK2) have been identified at high prevalence both in familial and sporadic Parkinson’s disease (PD) patients. LRRK2 is a 280 kDa enzyme that, besides a protein kinase domain, contains leucine-rich repeats, a GTPase domain, a COR domain and a WD40 motif. Mutations within each of these domains are linked with PD and several mutations result in increased kinase activity indicating a toxic gain-of-function. Thus far LRRK2 activity has only been assessed by autophosphorylation and phosphorylation of artifical substrates, which is catalysed rather slowly. We undertook a KESTREL screen in rat brain extracts to identify potential physiological protein substrates that are phosphorylated by the most prevalent LRRK2(G2019S) mutant. This led to the finding that two protein families that modulate interactions and dynamics of the actin cytoskeleton are efficiently phosphorylated by LRRK2. We mapped the phosphorylation site in one family by tandem mass spectrometry and showed that LRRK2 also phosphorylated a peptide fragment encompassing this site. These findings will be useful for the development of a high-throughput screening assay for small molecule LRRK2 inhibitors and also provide insight how deregulated LRRK2 activity might contribute to the early loss of dopaminergic axon in PD.
Speaker Bio:
Frank Gillardon obtained a masters’ degree in Biology from the University of Tuebingen, Germany. In 1992, he received his Ph.D. in Physiology from the University of Heidelberg, Germany where he focussed on neuronal apoptosis and cerebral ischemia. From 1996 to 1998 he worked as a lab head at the Max-Planck-Institute for Neurological Research, Cologne, Germany in the department of Prof. K.-A. Hossmann. He then joined Boehringer Ingelheim Pharma’s CNS Research to identify therapeutic targets in Alzheimer’s and Parkinson’s disease.

8:30 Targeting Cerebrovascular Rho-kinase in Stroke
Cenk Ayata, M.D., Harvard University

9:00 LRRK2 as a Therapeutic Target in Parkinson’s Disease
Andrew West, Ph.D., Instructor, Department of Neurology, Johns Hopkins University
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene initiate a highly penetrant phenotype clinically and neurochemically indistinguishable from idiopathic, late-onset Parkinson’s disease (PD). Missense mutations, occurring most often in enzymatic and evolutionarily conserved protein domains, represent the most common known cause of PD, including 1-2% of all sporadic PD and up to 40% of cases in select populations. The LRRK2 and LRRK1 proteins uniquely encode both a GTPase and kinase domain within the same open-reading frame, an arrangement highly evolutionarily conserved. Biochemical dissection of the LRRK2 protein reveals an intrinsic regulation of kinase activity via GTPase activity. Mutations associated with PD increase kinase activity in vitro, often through perturbation of upstream GTPase activity. While the LRRK2 kinase domain possesses highest sequence similarity to members of the mixed-lineage kinase protein family, a sub-class of MAPKKK proteins, LRRK2 does not obviously fit into the three-tiered MAPK pathway. Rather, LRRK2 is a serine/threonine kinase highly sensitive to both peroxide exposure and serum stimulation, capable of inducing neurotoxicity. In contrast, over-expression of kinase dead protein is well tolerated, implicating kinase activity both in susceptibility to PD and neurotoxicity in vitro. Therefore, small-molecule inhibition of LRRK2 kinase activity presents a novel therapeutic approach potentially capable of mitigating neurodegeneration in related disorders.
Speaker Bio:
Andrew West graduated magna cum laude with a bachelor’s degree in biochemistry from Alma College, Alma Michigan. He went on to earn a Ph.D. from the Mayo Clinic College of Medicine in Rochester, Minnesota. His work focused on the genetics of neurodegeneration and the molecular pathways of Parkinson’s disease in the laboratories of John Hardy and Matt Farrer in Jacksonville, Florida. He then completed a one-year post-doctoral fellowship in the laboratory of Nigel Maidment at University of California, Los Angeles, studying novel techniques in neurochemistry and viral transduction approaches. Subsequently, Andrew joined the laboratories of Ted and Valina Dawson at the Johns Hopkins University investigating the molecular basis of Parkinson’s disease and novel therapeutic avenues. He is currently an Instructor in the department of neurology at Johns Hopkins.

9:30 A Novel Role of CaMKII as a Postsynaptic Structural Protein
Yansnori Hayashi, M.D., Ph.D., Assistant Professor of Neurobiology, MIT

10:00 Refreshment Break

Session IV: Kinase Targets and Inhibitors in Inflammatory Disorders

a Structure-guided Design of Aminopyrimidine Bis-aryl Amides as Potent, Selective Inhibitors of Lck
Erin DiMauro, Ph.D., Senior Scientist, Medicinal Chemistry, Amgen, Inc.
The lymphocyte-specific kinase (Lck), a member of the Src family of cytoplasmic tyrosine kinases, is expressed in T cells and natural killer (NK) cells. Genetic evidence, including knockout mice and human mutations, demonstrates that Lck kinase activity is critical for normal T cell development, activation, and signaling. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T cell-mediated autoimmune and inflammatory disease. With the aid of X-ray structure-based analysis, aminopyrimidine bis-aryl amides 2 were designed from aminoquinazolines 1, which had previously been demonstrated to exhibit potent inhibition of Lck and T cell proliferation. Herein, we describe the synthesis and structure-activity relationships of a series of novel aminopyrimidine bis-aryl amides, possessing exceptional in vitro mechanism-based potency and improved selectivity profiles relative to their aminoquinazoline predecessors. Orally bioavailable compound 3 exhibited anti-inflammatory activity (ED50 9.4 mg/kg) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.
Speaker Bio:
In 1998, Erin received a B.S. in Chemistry from Wesleyan University, where she conducted research in synthetic organic chemistry with Professors Peter Jacobi and Albert Fry. In 2003, Erin obtained a Ph.D. in organic chemistry from the University of Pennsylvania, where she worked on bifunctional asymmetric catalysis with Professor Marisa Kozlowski. Erin is currently a Senior Scientist in Medicinal Chemistry at Amgen in Cambridge, MA. Her research efforts have focused on neuroscience and inflammation targets.

a Designing Selectivity, Potency and Oral Efficacy in the Discovery of New p38 MAP Kinase Inhibitors
Ravi Natarajan, Research Fellow, Merck & Co.
p38 (a mitogen-activated protein kinase) has been shown to play a key role in the release of cytokines such as TNF- and IL-1? from monocytes in signaling cascades that are initiated due to extra cellular stress stimuli. Inhibition of p38 activity is expected to regulate the levels of TNF-? and IL-1? thereby alleviating the effects of inflammation in RA. A new class of highly potent and selective p38 inhibitors based on the naphthyridininone scaffold have been discovered. X-ray crystallography and site directed mutagenesis studies were critical tools that aided the evolution of the naphthyridinone lead class starting from a pyrido-pyrimidinone template.
This presentation will discuss the derivation of key benchmark pre-clinical candidates in these novel scaffold classes (shown below) as influenced by structural biology studies, mutagenesis data and molecular modelling. efficacy studies in animal models for benchmark compounds will also be presented.
Speaker Bio:
Dr. Natarajan completed his undergraduate work in chemistry at the University of Bombay in 1988 and obtained a masters' degree from the prestigious Indian Institute of Technology in 1990. He joined the labs of Prof. David Crich at the University of Illinois in Chicago and graduated with a doctrate in 1996 after working in the area of Taxol Total synthesis. After a brief post-doctoral stint in the labs of Professor KC Nicolaou at the Scripps Research Institute, where he accomplished the total synthesis of Vancomycin, one of the last line of defence against staph-infection, he accepted a posistion at Merck Research laboratories in Rahway, NJ. He has worked at Merck for 8 years on various drug discovery programs spanning inflammatory diseases and ion channels. He is currently a Research fellow at Merck.

11:30 Kinase Inhibitors as Therapeutics for Chronic Inflammatory Diseases
Maria Webb, Ph.D., VP Preclinical Research, Biological & Pharmacological Sciences, Pharmacopeia
Kinase inhibition for treatment of chronic inflammatory and immunologic diseases eg RA, psoriasis, and transplant rejection require great selectivity for the target kinase. Among the issues to address are 1) how to find selective hits from screens, and 2) whether to assess selectivity by enzymology, cell biology or in vivo. A class of p38 kinase inhibitors possessing strong selectivity for p38?/? was discovered through screening. A triaminotriazine library showed good activity with notable selection that 118 of 123 active compounds contained a 3-amino-4-methylbenzamide substituent. Characterization of the hits demonstrated good kinase selectivity. Replacement of the triazine with cyanopyrimidine maintained kinase selectivity while improving other properties. In over 25 kinase screens, the methylbenzamide has not re-appeared in the hits. These data indicate an interaction critical for p38 selectivity that was apparent from screening through clinical development. The Jak kinases demonstrate a need for several assays to assess selectivity. Kinase activity, dependent upon [ATP], construct, and other factors, often does not track with downstream cell biology. Data will be shown to support the contention that assessment of Jak3:Jak2 selectivity is better achieved with stat5-PO4n than cell proliferation. Furthermore, in our kinase assays, PS020613 and CP-690,550 demonstrated only 2-fold selectivity for Jak3 over Jak1. These data support the notion that one must use several approaches to discern kinase selectivity.
Speaker Bio:
Maria Webb is Vice President of Pre-Clinical Research, Biology and Pharmacology Sciences, at Pharmacopeia in Princeton, NJ. She received her Ph.D. in 1983 in Physiology from The Pennsylvania State University where she worked on steroid receptor physiology. From 1983 to 1985 she was an NIH fellow in Dr. Gerald Litwack’s lab at Temple University Medical School where she worked on steroid receptor biochemistry. In 1985, she moved to Hershey Medical Center of The Pennsylvania State University where she was a Research Assistant Professor working in steroid receptor regulation of gene transcription. In 1989, she joined Bristol-Myers Squibb’s Cardiovascular Pharmacology department focusing on thromboxane, angiotensin II, endothelin and chemokine receptors before coming to Pharmacopeia in 1996 to build that company’s drug discovery capabilities and programs. Since joining Pharmacopeia, Dr. Webb has been involved in the development of several clinical candidates.

12:00 Lunch

1:00 Oral Presentations from Submitted Abstracts
Abstract Deadline: April 31
Submit an abstract to be considered for a short oral presentation

a Mechanisms of the Joint-Protective Effects of p38 MAPK Inhibitors in Rodent Arthritis
Gabriel Mbalaviele, Department of Inflammation, Pfizer, Inc.
Mitogen-activated protein kinase (MAPK) pathways are implicated in inflammatory diseases, including rheumatoid arthritis (RA). Though p38 MAPK (p38) participates in signaling cascades leading to joint destruction in arthritis, the mechanisms of its actions in this process remain incompletely understood. To address this issue, we developed a panel of potent and selective p38 inhibitors, including SC-409, and determined their effects on bone and cartilage degradation both in vitro systems and in vivo in rodent models of arthritis. This presentation will be focused on the actions of SC-409, and will provide evidence that this inhibitor spares joints from destruction by modulating the production and signaling functions of key inflammatory mediators such as TNF-? and receptor activator of NF-?B ligand (RANKL). The molecular mechanisms of p38 actions will also be discussed.
Speaker Bio:
Gabriel Mbalaviele received his Ph.D. degree in Developmental Physiology from the University of Paris 7, France in 1992. He went on to conduct his post-doctoral fellowship in calcium and bone metabolism in Gregory Mundy’s lab at the University of Texas Health Science Center at San Antonio, TX. He then joined Osiris Therapeutics, Baltimore, MD, investigating the utility of human adult bone marrow-derived mesenchymal stem cells in the generation of connective tissues. In 2000, Gabriel joined the Inflammation department at Pharmacia Corporation/Pfizer Inc., St Louis, MO, where is currently a Sr. Principal Scientist. He is also an Adjunct Assistant Professor of Medicine at Washington University School of Medicine, St Louis, MO, where he studies the mechanisms that control osteoblast cell fate determination from multipotent skeletal stem cells.

2:00 IKK2 Inhibition in Preclinical Models of Rheumatoid Arthritis
Elena Izmailova, Ph.D., Senior Scientist, Millennium Pharmaceuticals, Inc.

Session V: Role of Kinases in Other Therapeutic Disorders

a Inhibitors of Case in Kinase 1 Block the Growth of Leishmania Major Promastigotes In Vitro
John Allocco, Research Associate, Department of Animal and Human Parasitology, Merck & Co.
We have recently described the antiparasitic activity of trisubstituted pyrrole and imidazopyridine protein kinase inhibitors against Eimeria spp., Toxoplasma gondii and Plasmodium falciparum protozoan parasites. Genetic and biochemical data demonstrate that cGMP-dependent protein kinase (PKG) is the primary molecular target of these antiparasitic compounds. We extend these original observations and now report that both kinase inhibitor scaffolds inhibit the growth of Leishmania major promastigotes and Trypanosoma brucei blood stream forms in vitro. Genome informatics predicts that neither of these trypanosomatid parasites codes for a PKG orthologue. Biochemical studies have led to the discovery that casein kinase 1 (CK1) is the target of these kinase inhibitors in the trypanosomatid parasites. CK1 activity from extracts of L. major promastigotes co-fractionates with [3H]-imidazopyridine binding activity. Further purification of CK1 activity from L. major and characterization via LC-MS/MS identified CK1 isoform 2 as the specific parasite protein associated with the imidazopyridine ligand. L. major CK1 isoform 2 expressed as a recombinant protein in E. coli shares biochemical and compound sensitivity profiles similar to the purified native enzyme. As novel chemotherapeutic treatment options for trypanosomatid parasites are in enormous demand, the results described here warrant further evaluation of the activity of these compounds in models of infection, as well as studies to genetically validate CK1 as a therapeutic target.
Speaker Bio:
John Allocco received a B.Sc. degree in 1981 from Hunter College City University of New York. He began his professional career in 1981 in the Nussenzweig lab in the Department of Pathology at New York University Medical Center. The research focus in the lab was on human parasitic diseases such as malaria and trypanosomiasis and opportunities for immune intervention. To that end he was involved in the discovery and characterization of antigenic proteins that were used to develop malaria vaccines for studies in chimpanzees and eventually in man. John joined Merck & Co. in 1989 in the Department of Animal and Human Parasitology. The discovery of novel antiparasitic chemotherapeutics and mechanism of action studies have been John's primary research interest at Merck. He was involved in the discovery and validation of (i) the Mannitol Cycle in Eimeria spp. parasites, a parasite-specific glycolytic pathway, (ii) apicidin, a natural product inhibitor of parasite histone deacetylase, and (iii) small molecule inhibitors of parasite cGMP-dependent protein kinase (PKG).

3:00 TBA
Julia Billiard, Ph.D., Senior Scientist II, Women's Health Research Institute, Wyeth Research
Speaker Bio:
Dr. Julia Billiard received her Masters degree in Physics from the Leningrad Polytechnic Institute (Russia) and her Ph.D. in Physiology and Biophysics from the University of Washington in 1997. During her Ph.D. training, she was investigating the hormonal regulation of exocytosis in the pituitary cells. She did post-doctoral research with Dr. Peter Rotwein at Oregon Health and Sciences University studying mechanisms of regulation of IGF-I gene expression in bone. Dr. Billiard joined Wyeth Research in 2001 where she is working in the department of Women’s Health and Musculoskeletal Biology. She is an inventor on 2 patents and an author of 15 original articles. In 2006, Dr. Billiard won a Science Spectrum magazine “Trailblazers” award for educational leadership and innovative thinking for women and minorities in science. She is a member of The American Society for Bone and Mineral Research, the Endocrine Society, and the New York Academy of Sciences.

3:30 A Discovery of an Orally Active and Highly Selective Small Molecule Inhibitor of the MET Receptor Tyrosine Kinase
Sean G. Buchanan, Ph.D., Senior Director, Discovery Biology, SGX Pharmaceuticals

4:00 Conference Concludes