DiscoveryOnTarget.comOrganized by Cambridge Healthtech Institute

10thAnnual

Sunday, September 3012:00 - 3:00 pm• Understanding Structure- and Fragment-Based Drug Discovery: Tools and Techniques

3:30 - 6:30 pm• Pre-Clinical Toxicity

• Understanding and Targeting Protein-Protein Interactions

Tuesday, October 2 6:30 - 9:00 pm• Allosteric Modulators: Putting Theory to Practice

Short Courses

3rd Annual | October 2-3, 2012

Advances in Targeting the PI3K Pathway

Inaugural | October 1-2, 2012

Targeting the Ubiquitin Pathway

6th Annual | October 1-2, 2012

Novel Strategies for Kinase Inhibitors

Part Of:

October 1-3, 2012Boston Marriott Copley Place | Boston, MA

Exploring Signaling Pathways

Monday

October 1Tuesday

October 2Wednesday

October 31 GPCR-Based Drug Discovery 6 Allosteric Modulators

2 Kinase Inhibitors 7 PI3K Pathway

3 Ubiquitin Pathway 8 Functional Genomics

4 Histone Deacetylases 9 Histone Methyltransferases and Demethylases

5 Cancer Cell Metabolism 10 Diabetes Targets

Event-at-a-Glance

2 | Discovery On Target

COrpOrate SpOnSOrS

Sunday, September 30

12:00 - 3:00 pmUnderstanding Structure- and Fragment- Based Drug Discovery: tools and techniques (SC1)Course Instructors:Daniel A. Erlanson, Ph.D., Co-Founder, Carmot Therapeutics, Inc. Alex Burgin, Ph.D., CSO, Emerald BiostructuresAdditional Instructor to be Announced

3:30 - 6:30 pmpre-Clinical toxicity (SC12Course Instructor:James Dykens, Ph.D., CEO, Eyecyte TherapeuticsAdditional Instructor to be Announced

Understanding and targeting protein-protein Interactions (SC4)Course Instructors:Sandor Vajda, Ph.D., Professor, Biomedical Engineering and Chemistry, Boston UniversityAdrian Whitty, Ph.D., Associate Professor, Chemistry, Boston University

tueSday, OctOber 2

6:30 - 9:00 pmDInner SHOrt COUrSe: allosteric Modulators: putting theory to practice (SC6)Course Instructors: Arthur Christopoulos, Ph.D., Professor, Department of Pharmacology, Monash UniversityAnnette Gilchrist, Ph.D., Assistant Professor, Pharmaceutical Sciences, Midwestern University

* Separate Registration Required

Short Courses*

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6th Annual | October 1-2, 2012

Novel Strategies for Kinase InhibitorsEmerging Targets for the Pipeline

4 | Discovery On Target

mOnday, OctOber 1

7:00 am Conference registration and Morning Coffee

novel (non-Oncology) applications8:30 Chairperson’s Opening remarks8:40 novel Opportunities for Kinases in OphthalmologyAndy Whitlock, Ph.D., Director, Pre-Clinical Development, Ora, Inc.Ocular anterior segment diseases, such as allergic conjunctivitis, dry eye and post-operative inflammation need new potent treatments with efficacy comparable to steroids but very limited side effects. Recently, a number of new kinase inhibitors have been studied in more detail for conditions such as cancer and rheumatoid arthritis. The mechanisms of action of these novel therapies are very applicable to a number of ophthalmic diseases that are underserved with current treatments.

9:10 targeting the Malaria KinomeAndrew Tobin, Ph.D., Professor of Cell Biology, Cell Physiology and Pharmacology, MRC Toxicology Unit, University of LeicesterWe have just published in Nature Communications ((2011) Nat Commun 2, 565-576) a paper describing the essential protein kinases in the human malaria parasite Plasmodium falciparum. In collaboration with Monash University, the structural genomics consortium in Toronto and a major pharmaceutical company we are now developing novel protein kinase inhibitors that selectively target the malaria kinome.

9:40 rC Kinase: a novel target Implicated in COpD and Idiopathic pulmonary FibrosisStefen A. Boehme, Ph.D., Director, Immunology, Axikin PharmaceuticalsWe have characterized a novel serine/threonine protein kinase, called RC kinase. Inhibition of RC kinase by siRNA or novel small molecule inhibitors reduces pulmonary inflammation and cellular and biochemical markers of disease in murine models of both COPD and IPF. We will discuss our ongoing preclinical development of antagonists against this novel kinase and their utility as a possible treatment for COPD and IPF.

10:10 Coffee Break in the exhibit Hall with poster Viewing

targeting Kinases from Different Vantages10:40 Chemoproteomic approaches to target Deconvolution and Selectivity profiling of Kinase InhibitorsMarkus Schirle, Senior Investigator I, Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Inc.Quantitative chemoproteomics allows the determination of protein interaction profiles of drug candidates in a disease-relevant cell line or tissue. In contrast to standard biochemical and biophysical kinase

assays, application of this method to kinase inhibitors determines compound binding to endogenously expressed kinases under conditions approximating the physiological situation with regard to the molecular state of the kinase and presence of required co-factors and regulatory proteins. Different experimental variants and applications of this approach will be presented.

11:10 Use of cHtS for Identification Sponsored by of Synergistic Drug Combinations that are Selective and Kill Cancer CellsRichard Rickles, Ph.D., Senior Research Fellow Oncology & Director, Discovery Partnerships, Zalicus Inc.Monotherapies are rarely effective cancer treatments as tumor cells have a tremendous capacity to overcome the activity of single drugs. Understanding the multi-target mechanisms for selective killing is required for oncology drug discovery. We have developed a cHTS platform for the rapid screening of thousands of drug combinations in hundreds of cell lines to identify potent drug combinations that selectively kill tumor cells. The platform is a powerful tool for both discovery and translational research.

11:40 the nanocyclix platform: applications on novel Kinase targets in Cancer, CnS and epigeneticsJan Hoflack, Ph.D., CSO, Drug Discovery, Oncodesign BiotechnologyOncodesign's Nanocyclix platform gives access to potent and selective inhibitors for known and unexplored kinases. Broad profiling and phenotypic screening approaches will be described that have led to advanced programs in cancer, CNS, inflammation and epigenetics fields. The compounds display unique properties as related to ADME profiles and CNS penetration.

12:10 pm Biophysical and Mechanistic Insights into a novel allosteric Inhibitor of Spleen tyrosin KinaseJustin Hall, Ph.D., Senior Scientist, Structural Biology and Biophysics, PfizerKinases play essential roles in cell signal amplification and transduction and are important targets in oncology and inflammation. Due to the conservation and prevalence of the kinase domain motif (ca. 520 different proteins), it is a substantial challenge to develop ATP competitive inhibitors against a specific target while also simultaneously out-competing physiological concentrations of ATP. Recourse to this challenge is the development of allosteric kinase inhibitors that are noncompetitive against ATP; we show here a novel allosteric inhibitor of spleen tyrosine kinase (Syk) that may help the development of human therapeutics.

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12:40 LUnCHeOn preSentatIOn Sponsored by

a novel approach for the Study of Kinase Signal transduction – Comparative Measurement of in vitro and in vivo expression of MapK pathway KinasesW. Matthew Dickerson, Ph.D., Senior Scientist, Assay Development, BioScale, Inc.The ability to measure the activation states and molecular interactions of the kinases comprising the MAPK and PI3K-AKT pathways are crucial in the efficient and effective discovery and development of anti-cancer pharmaceuticals and therapeutics. Results of the assessment and quantification of EGFR, MEK, ERK, p38, JNK and AKT in several tumor cell lines with or without stimulation of surface ligand receptors, and compared with lysates prepared from xenograft tumors derived from the same cell lines will be discussed.

emerging therapeutic targets2:20 Chairperson’s remarks2:25 protein Kinase CK2, a Logical therapeutic target for Drug CombinationsDenis Drygin, Ph.D., Vice President, Biology, Cylene PharmaProtein kinase CK2 controls multiple biological pathways that are necessary for the maintenance of malignant phenotype. Increased expression levels and/or activity of CK2, which are commonly found in cancers, have been linked to poor prognosis and drug resistance, highlighting the potential of CK2 as a therapeutic target in drug combinations. I will discuss known mechanisms that underlie the regulation of drug resistance by CK2, present examples of the enhancement of therapeutic outcome by modulation of CK2 expression and/or activity, and provide a perspective on the potential use of CK2 inhibitors for the clinical development in combination with other therapeutics.

2:55 repurposing Kinase Medicinal Chemistry for neglected Diseases Caused by protozoan parasitesMichael Pollastri, Ph.D., Associate Professor, Chemistry & Chemical Biology, Northeastern University

3:25 refreshment Break in the exhibit Hall with poster Viewing4:05 a Synthetic Lethal and Survival rnai Screen accompanied by Cancer Drug neratinib Identifies novel Oncology targets Leading to neratinib and paclitaxel Combination treatments and Markers of Drug resistanceAttila Seyhan, Ph.D., Senior Biomarker Discovery and Development Leader, formerly at Translational Immunology, Biotherapeutics Clinical R&D, Pfizer, Inc.We undertook a genome-wide pooled lentiviral RNAi screen in comibantion with neratinib, a tyrosine kinase inhibitor of the ErbB receptor family currently in Phase III clinical trials, and discovered a panel of genes whose inhibition selectively impaired or enhanced the viability of cancer cells in the presence of subeffective or lethal concentrations of neratinib.

4:35 the Discovery of potent and Selective Inhibitors of CK2 Kinase Identified through Focused Subset Screening and Structure Based DesignClaudio Chuaqui, Ph.D., Principle Scientist II, Astrazeneca R&D

In this talk I will describe the discovery of potent and selective CK2 inhibitors identified via kinase-focused subset screening as starting points for structure-based design. The synthesis, SAR, and effects of this novel series on Akt signaling and cell proliferation in vitro are described.

5:05 Interactive Breakout Discussion Groups the Challenge of Drug resistanceModerator: David Proia, Ph.D., Senior Scientist, Synta Pharmaceutical• Establishing drug resistance using in vitro models• Identifying the mechanisms of resistance and ways to bypass• Translation in vivo and in the clinic

Drug Combination therapies – pro’s and Con’s to ConsiderModerator: Denis Drygin, Ph.D., Vice President, Biology, Cylene Pharma• Challenges in the identification of clinically significant

“Synthetic Lethality”• Multi-targeted agents vs combination of selective agents• Minimizing side-effects and toxicity of drug combinations

atp non-Competitive InhibitorsModerator: Justin Hall, Ph.D., Senior Scientist, Structural Biology and Biophysics, Pfizer• Kinase active site anatomy; which residues are broadly

conserved and how is inhibitor selectivity built?• The kinase domain in contexts; why do we usually study isolated

the kinase domains and what can we gain from looking at larger constructs?

6:15 – 7:30 Welcome reception in the exhibit Hall with poster Viewing

tueSday, OctOber 2

7:30 am Breakfast presentation (Sponsorship Opportunity Available) or Morning Coffee

Drug resistance8:15 Chairperson’s Opening remarks8:20 Overcoming resistance to Kinase Inhibitors with the HSp90 Inhibitor GanetespibDavid Proia, Ph.D., Senior Scientist, Synta PharmaceuticalWith the approval of an ALK (Xalkori) and BRAF (Zelboraf) inhibitor, the year 2011 continued to show the importance of making cancer treatment decisions based on the molecular features of tumors. However, the development of drug resistance still remains a hurdle. In this presentation, we will show that the Hsp90 inhibitor ganetespib displays potent preclinical activity in a broad spectrum of tumor cells with acquired and/or intrinsic resistance to kinase inhibitors, including those driven by ALK and BRAF. We also present encouraging results from our recent clinical trials.

6 | Discovery On Target

8:50 FeatUreD preSentatIOn

Dynamic reprogramming of the Cancer Kinome in response to targeted Kinase InhibitionGary L. Johnson, Ph.D., Kenan Distinguished Professor and Chair, Department of Pharmacology, University of North Carolina School of Medicine We have developed chemical proteomic methods to define the activity of a significant percentage of the kinome expressed in cancer cells and tumors. The method uses Multiplexed Inhibitor Beads coupled with quantitative Mass Spectrometry (MIB/MS), which allows us to study the activation state of over 60-70% of the expressed kinome simultaneously. MIB/MS analysis defines systems kinome reprogramming in response to highly selective inhibitors that creates inhibitor resistance.

9:20 Utilizing Kinase Cell-Based Selectivity for Drug Discovery: pim as a Case StudyDeborah J. Moshinsky, Ph.D., Founder and President, Cell Assay Innovations, LLC

9:50 Coffee Break in the exhibit Hall with poster Viewing

novel Inhibitors – Fresh from the press10:40 the regulation of tnF-Induced necrosis by rIp Kinases and MLKLZheng-Gang Liu, Ph.D., Senior Investigator, Cell and Cancer Biology Branch, Center for Cancer Research, NCI, NIHTumor necrosis factor (TNF) is a proinflammatory cytokine that plays a

critical role in diverse cellular events, including necrosis and apoptosis. Although the mechanism of TNF-induced apoptosis is well understood, the regulation of necrosis is still elusive. Recently, it has been found that RIP kinases, RIP1 and RIP3, play an essential role in this process and that the newly identified protein, MLKL, is a key downstream component of RIP kinases in TNF-induced necrosis.

11:10 Case-Studies From the Discovery and Optimization of novel Inhibitors which exploit the atp-Incompatible Conformations of Inactive protein KinasesSudharshan Eathiraj, Ph.D., Lead Investigator, ArQule Inc.Kinases in the autoinhibited state adopt structurally diverse and distinct conformations, and serve as intrinsic negative regulatory mechanism for kinase activation by preventing access to ATP and/or substrate binding. Recent work at ArQule has utilized a growing understanding of how the autoinhibitory conformation of apo-kinases can be exploited for the identification and optimization of inhibitors. The ATP-binding cleft in the autoinhibited state of a kinase is frequently associated with hydrophobic residues which cluster into an ATP-incompatible non-polar region. Inhibitors have been designed using in silico methodology and an assay platform assembled to identify these inhibitors. This rational structure-based drug design technology has been successfully employed for number of kinase targets across multiple families. This presentation will present case-studies from this work illustrating how these inhibitors have been characterized using biophysical, biochemical and cell-based assays together with X-ray crystallographic and mutational studies.

11:40 talk title to be announcedCampbell McInnes, Ph.D., Associate Professor, South Carolina College of Pharmacy, University of South Carolina

12:10 pm Close of Conference

Inaugural | October 1-2, 2012

Targeting the Ubiquitin PathwayDiscovery and Development of Novel Inhibitors

mOnday, OctOber 1

7:00 am Conference registration and Morning Coffee

Ubiquitin perspectives8:30 Chairperson’s Opening remarks

8:40 roles of Ubiquitin and Ubiquitin-Like proteins in autophagyVladimir Kirkin, Ph.D., Senior Scientist, Merck-Serono; Research & Early Development, Oncology Platform, In Vivo Pharmacology, Merck KGaAAutophagy can be a highly selective process, whereupon deleterious structures (protein aggregates, damaged mitochondria or microbes) are recognized, sequestered by the nascent autophagosome from the rest of the cytosol and delivered to the lysosome for degradation. Ubiquitination is a crucial modification responsible for labeling

autophagic substrates and targeting autophagosome formation to a specific site in the cell. On the autophagosome’s side, ubiquitin-like proteins LC3/GABARAP covalently attached to the vesicle, are equally important for the target-induced autophagosome formation. Selective autophagy receptors, such as p62/SQSTM1, by binding both ubiquitin and LC3/GABARAP, can provide the bridge between the ubiquitinated cargo and the autophagosome formation and thus represent a class of emerging drug targets relevant to infection diseases, neurodegeneration and cancer.

9:10 Ubl peptidase in Human protozoan parasite Leishmania donovani as a potential Drug targetSreenivas Gannavaram, Ph.D., Scientist, Division of Emerging and Transfusion Transmitted Diseases, OBRR/CBER/FDAUbl's regulate/modify the functions of a wide range of proteins. In our laboratory we have identified Ufm1 mediated protein conjugation to be essential for Leishmania amastigotes, the parasite stages found in human host. Therefore, proteases associated with Ufm1 conjugation activities can provide for potential new drug

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targets to combat human leishmaniasis because of lack of vaccines and increasing drug resistance to a few existing drugs against Leishmania. Results on the characterization of Ufm1 associated peptidase will be discussed.

9:40 advancing Drug Discovery in the Ubiquitin pathwayBen Nicholson, Ph.D., Director, Biology, ProgenraProgenra and their partners have been working to address the challenges of identifying small molecule inhibitors of both deubiquitylating enzymes and E3 ligases by developing novel assay formats. Specifically, data will be presented highlighting Progenra’s novel deubiquitylating enzyme and E3 ligase assay formats. Furthermore, specific examples of Progenra’s diverse drug discovery projects will be presented, confirming Progenra’s ability to identify novel modulators of these highly relevant therapeutic pathways.

10:10 Coffee Break in the exhibit Hall with poster Viewing

targeting the proteasome System10:40 Developing allosteric Inhibitors targeting the proteasome assembliesMaria Gaczynska, Ph.D., Associate Professor, Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San AntonioThe proteasome, with its modular structure and multiple activities is a perfect target for allosteric drugs. They may affect single activities or their combination, and may interfere with stability of higher-order proteasome assemblies. In particular, the interface between the core and regulatory modules is rich in allosteric hot spots. The novel approach of targeting the interface with allosteric ligands exhibiting anti-cancer or anti-inflammatory properties will be presented and discussed.

11:10 Degrading the Barriers to Sponsored by Drug Discovery in Ubiquitin e3 Ligase pathwaysBlaine N. Armbruster, Ph.D., Senior Manager, Discovery & Development Solutions, EMD Millipore Corporation

11:25 Sponsored presentation (Opportunity Available)

11:40 Oncogenic transcription Factor FOXM1 is a Major target for proteasome InhibitorsAndrei Gartel, Ph.D., Associate Professor, Medicine, University of IllinoisThe oncogenic transcription factor Forkhead Box M1 (FoxM1) is overexpressed in a majority of human cancers, while its expression is usually low in normal cells. All tested proteasome inhibitors target transcriptional activity and expression of FOXM1 in human cancer cells. Targeting of FOXM1 contributes to anticancer activity of proteasome inhibitors and may explain why they selectively kill cancer, but not normal cells. We propose a novel universal mechanism of FOXM1 suppression by proteasome inhibitors.

12:10 pm enhancement of proteasome activity by a Small-Molecule Inhibitor of USp14Daniel Finley, Ph.D., Professor, Cell Biology, Harvard Medical SchoolUsp14 inhibits proteasomes, by trimming the substrate’s ubiquitin chain, leading to substrate release from the proteasome before it can be degraded. A high-throughput screen identified a selective, small-molecule inhibitor (IU1) of Usp14. Treatment of cells with IU1 accelerated degradation of several proteins that have been implicated in neurodegenerative disease. Thus, proteasomes function under tonic inhibition by the deubiquitinating activity of Usp14.

12:40 Luncheon presentation (Sponsorship Opportunity Available) or Lunch on Your Own

Ubiquitin Ligases2:20 Chairperson’s remarks

2:25 FeatUreD preSentatIOn

Ubiquitin and er Quality ControlHidde Ploegh, Ph.D., Member, Whitehead Institute for Biomedical Research, Professor of Biology, Massachusetts Institute of Technology

2:55 targeting Iap proteins: Ubiquitin Ligases at the Crossroads of apoptosis, Inflammation and CancerDomagoj Vucic, Ph.D., Senior Scientist, Early Discovery Biochemistry, Genentech, Inc.Inhibitor of apoptosis (IAP) protein family members block cell death in response to diverse stimuli and are expressed at elevated levels in many human cancers. We have designed small-molecule IAP antagonists that bind to IAP proteins resulting in a dramatic induction of c IAP auto-ubiquitination and rapid proteasomal degradation as well as inhibition of tumor growth in vivo. Understanding the significance of IAP E3 ligase activity is important for the design of novel therapeutics for the treatment of cancers.

3:25 refreshment Break in the exhibit Hall with poster Viewing

4:05 Identification of e3 Ubiquitin Ligase Substrates through Quantitative proteomicsJohn Doedens, Ph.D., Scientist, Resolve TherapeuticsIdentification of substrates for the diverse repertoire of E3 ubiquitin ligases encoded in the human genome remains a significant challenge for the field. We have applied protein-level and peptide-level enrichment strategies combined with siRNA technology, SILAC, and quantitative mass spectrometry to identify substrates of the E3 ligase HRD1, an E3 proposed to function in the pathogenesis of rheumatoid arthritis. Validation of these methods and the identified substrates will be discussed.

8 | Discovery On Target

4:35 Diverse routes to the proteasome: role of SUMO-Specific Ubiquitin LigasesJuergen Dohmen, Ph.D., Professor, Genetics, University of CologneThe 26S proteasome of eukaryotic cells mediates the degradation of a diverse array of proteins. In most cases, degradation is promoted by poly-ubiquitylation of the substrate proteins. In other cases, however, proteins are degraded without prior modification. Ubiquitin-dependent degradation is moreover involved in the control of proteins that carry other ubiquitin-related modifiers such as SUMO. This process involves the activity of specialized ubiquitin ligases that recognize and ubiquitylate poly-sumoylated proteins, and thereby mediate their degradation by the proteasome. Recognition and targeting of sumoylated proteins by these ligases can be inhibited by competition with polypeptides bearing SUMO interaction motifs (SIMs).

5:05 Interactive Breakout Discussion Groups

Challenges of Identifying e3 LigasesModerator: Ben Nicholson, Ph.D., Director, Biology, Progenra

progress in Developing therapeuticsModerator: Philippe Nakache, Ph.D., Head, Chemistry, Proteologics, Ltd

allosteric Inhibitors – What is the advantage?Moderator: Maria Gaczynska, Ph.D., Associate Professor, Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio

6:15 – 7:30 Welcome reception in the exhibit Hall with poster Viewing

tueSday, OctOber 2

7:30 am Breakfast presentation (Sponsorship Opportunity Available) or Morning Coffee

exploring novel Strategies8:15 Chairperson’s Opening remarks

8:20 Development of a novel Selective Inhibitor of posh for the potential treatment of Cancer and Inflammatory DiseasesPhilippe Nakache, Ph.D., Head, Chemistry, Proteologics, LtdThe presentation will describe the development of a new inhibitor of POSH and describe the results available so far in in vitro and in vivo studies.

8:50 talk title to be announcedPaul Andrews, Ph.D., Scientist, Amgen (tentative)

9:20 a novel Bacterial Genetic System to Identify new targets and Leading Drugs of the Ubiquitin pathwaysGali Prag, Ph.D., Principal Investigator, Department of Biochemistry and Molecular Biology and the Institute for Structural Biology, Tel Aviv University

The action of deubiquitylating enzymes, and the immense number of E3-ligases and substrates, all pose challenges to assign particular substrates to specific E3s. To circumvent this limitation we developed a reconstituted genetic system for ubiquitylation in E.coli. In-frame tethering a split reporter gene onto the ubiquitylation cascade facilitates the screening of selected components. The use of the system for identification of new targets and leading drugs discovery will be demonstrated.

9:50 Coffee Break in the exhibit Hall with poster Viewing

10:40 Ubiquitin pathway-related target Finding in the Context of WntFeng Cong, Ph.D., Scientist, NovartisPerturbation of Wnt signaling can lead to degenerative diseases and tumorigenesis, while agents that restore balance to Wnt signaling pathway output are predicted to have therapeutic value in such disease states. Using genetic and chemical genetic screens, we have identified tractable targets of the ubiquitin system that regulate the stability of Axin and Frizzled, two core components of the Wnt pathway. Molecular characterization and therapeutic exploration of these regulatory mechanisms will be discussed.

11:10 Deubiquitinating enzymes as Drug targets in CancerSebastian Nijman, Ph.D., Principal Investigator, Chemical Genomics, The Research Center for Molecular Medicine, Vienna, AustriaTargeting enzymes involved in the ubiquitin machinery is receiving increasing attention as a strategy to treat cancer. We have recently found that the Ubiquitin protease USP4 regulates the master kinase PDK1 and have developed screening strategies to identify cancer cell vulnerabilities involving other deubiquitinases. In addition, I will present a novel technology to perform human test tube to discover drug targets, including the generation of a genome-wide collection of knockout cells.

11:40 Cancer Cell resistance to the neDD8-activating enzyme Inhibitor MLn4924Matthew D. Petroski, Ph.D., Assistant Professor, Sanford-Burnham Medical Research InstituteMLN4924, developed by Millennium Pharmaceuticals, is a first-generation NAE inhibitor in clinical development for hematological and advanced non-hematological malignancies. Using an in vitro cancer cell selection strategy, we have discovered on-target mutations that decrease sensitivity to the molecule. I will describe our characterization of MLN4924 resistance mechanisms and discuss the implications on NAE and other activating enzymes as therapeutic targets.

12:10 pm Close of Conference

tueSday, OctOber 2

12:30 pm Conference registration

pI3K pathway perspectives1:30 Chairperson’s remarks

» 1:40 KeynOte preSentatIOnDonald Durden, M.D., Ph.D.,Vice Chair for Research, Department of Pediatrics, University of California San Diego; Associate Director, Pediatric Oncology, Moores UCSD Cancer Center

2:10 Discovery and Development of novel, Isoform-Selective pI3K Inhibitors for the treatment of Immune-Inflammatory Diseases and CancerStephen J. Shuttleworth, Ph.D., FRSC CChem, CSO, Karus Therapeutics Ltd.Our R&D programs at Karus are centered on the design and development of subtype-selective small molecule inhibitors of PI3K and of HDAC. This talk will outline our approaches to PI3K isoform-specific inhibitor discovery and development for the treatment of Th17 cell-mediated immune-inflammatory diseases, and of specific tumour types.

2:40 the mtOrs new Clothes-Questioning Dogma and Dispelling Myths Surrounding pI3K pathway InhibitionJoseph Garlich, Ph.D., Stemica LLCPreviously it was thought that many tumor types would be sensitive to PI3K pathway inhibitors but emerging biology has shown complex interactions including alternate pathway activation/resistance mechanisms exist to blunt the effects of these inhibitors. These new developments argue for inhibiting more kinase targets for best efficacy. PI3K isoform selective inhibition represents the "less is more" approach but several examples are now available to refute this line of attack demonstrating it to be less efficaceous. This and other ramifications of new pathway biology will be discussed.

3:10 refreshment Break in the exhibit Hall with poster Viewing

progress in targeting the pI3K pathway3:45 targeting the pDK1/akt Signaling pathwayJacques Ermolieff, Ph.D., Senior Principal Scientist, External Research Solutions (ERS), Pfizer Worldwide Research and Development

4:15 Sponsored presentations (Opportunities Available)

4:45 role of phosphoinositide 3-Kinase p110 Gamma in pancreatic and Liver CancerMarco Falasca, Ph.D., Professor in Molecular Pharmacology, Blizard Institute, Queen Mary University of LondonThe PI3K subunit p110alpha has a well established role in cancer and gain of function of this isoform, due to mutation is common in several human cancers. A role has been suggested for p110 gamma in tumour angiogenesis and drug resistance of chronic myeloid leukemia cells. Interestingly, overexpression of wild-type p110alpha does not appear to have transforming potential while overexpression of the wild-type catalytic subunits p110beta, gamma or delta is sufficient to induce an oncogenic phenotype in cultured cells. Accumulating evidence from our lab clearly indicate that p110 gamma plays a key and specific role in pancreatic and liver cancer.

5:15 targeting Specific Class I pI3K Isoforms for the treatment of B and t-Cell MalignancesBrian Lannutti, Ph.D., Associate Director, Cancer Research, Gilead Sciences, Inc.

5:45 end of Day

WedneSday, OctOber 3

8:00 am Interactive Breakfast Breakout Discussion Groups

Designing Selective InhibitorsModerator: Christoph M. Dehnhardt, Ph.D., Senior Principal Scientist, Pfizer Global R&D WWMC

Lessons Learned from the ClinicModerator: Joseph Garlich, Ph.D., Stemica LLC

targeting pI3K Delta - Challenges and progressModerator: Brian Lannutti, Ph.D., Associate Director, Cancer Research, Gilead Sciences, Inc.

non-Cancer applications for the pI3K pathway

9:05 Chairperson’s remarks

9:10 the regulation of Class III pI3KWen Jin Wu, Ph.D., Principal Investigator (PI), Division of Monoclonal Antibodies, Office of Biotechnology Products, Food and Drug Administration (FDA)VPS34, a class III PI3K, is a member of the PI3K family involved in vesicular trafficking, nutrient signaling, and autophagy. Recent studies suggest that VPS34 is upstream of mTOR. We found that Src

3rd Annual | October 2-3, 2012

Advances in Targeting the PI3K PathwayOptimizing Selectivity, Specificity and Efficacy

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phosphorylated VPS34, resulting in upregulation of VPS34 kinase activity. Most recently, we observed that while kinase activity of VPS34 measured by in vitro kinase assay may not be significantly upregulated by insulin, the cellular localization of VPS34 and localized production of PI3P by VPS34 was regulated by insulin. Our data suggest that VPS34 is downstream of insulin-coupled signaling and a potential therapeutic target for cancer therapy.

9:40 phylogenomics of phosphoinositide Lipid Kinases: a Drug Discovery perspectiveJames R. Brown, Ph.D., Computational Biology, Quantitative Sciences, R&D, GlaxoSmithKlinePhosphoinositide lipid kinases (PIKs) are key proteins for second messenger signalling and lipid metabolism. They are also an emerging class of drug targets for many diseases including cancer and inflammatory, metabolic and infectious diseases. This talk considers the phylogenomics of PIK protein families and their implications for drug discovery. Insights gained into the occurrence of oncogenic mutations, the polypharmacology of PIK inhibitors and opportunities to target malaria will be discussed.

10:10 Coffee Break in the exhibit Hall with poster Viewing

10:55 pharmacological targeting of SHIp-1: novel approaches to Manipulate pI3K Signaling in the Immune SystemStephen Ward, Ph.D., Professor, Inflammatory Cell Biology; Head of Pharmacology, Department of Pharmacy & Pharmacology, University of BathDysregulated PI3K signalling is associated with chronic inflammation and other immune-mediated disorders. Pharmacological activation of the lipid phosphatase SHIP-1 is a promising alternative to the direct inhibition of PI3K and offers selectively for targeting of the immune system because of its hematopoietic-restricted expression. The characterisation of small chemical entities that either activate or inhibit SHIP-1 and their impact on PI3K-dependent signaling and functions in leukocytes will be discussed.

11:25 the neuroprotective effects of progesterone through the phosphoinositide 3-Kinase/protein Kinase B Signaling pathwayIqbal Sayeed, Ph.D., Assistant Professor, Emergency Medicine, Emory University

11:55 Discovery of pI3K Inhibitors for the treatment of Cancer and Inflammatory DiseaseDavid J. Matthews, Ph.D., Vice President, Drug Discovery & Exploratory Development, Pathway Therapeutics, Inc.PI3K delta plays a fundamental role in the initiation and progression of many inflammatory and autoimmune diseases. We have discovered PWT143, a novel, highly selective PI3K delta inhibitor currently in pre-clinical development. PWT143 potently inhibits signaling in immune cells and has demonstrated compelling efficacy in rodent models of immune disease. Pre-clinical data and opportunities for clinical development will be presented.

12:25 pm Sponsored presentation (Opportunity Available)

12:40 LUnCHeOn preSentatIOn Sponsored by Development of the pI3K pathway Inhibitors: How to Choose the right Cell Line Fang Tian, Ph.D., Scientist, Cell Biology, ATCCThe PI3K signaling pathway is a major pathway involved in the regulation of cell proliferation, survival, and metabolism. The genetic alterations in this pathway, as well as in other signaling cascades, provide opportunities for the development of targeted cancer therapies by using single compound or multi-drug combinations. This talk will discuss how to choose the right human cancer cell lines as essential tools either in high-throughput drug screening or detailed molecular mechanism studies.

1:55 Chairperson’s remarks

2:00 Selective Inhibitors of pI3K Delta: Modulators of Immune Cell Function with potential for treating Inflammatory DiseasesKamal D. Puri, Ph.D., Senior Research Scientist II, Biology, Gilead Sciences Inc.PI3K delta regulates a variety of leukocyte functions including activation, proliferation, tissue homing, and the release of inflammatory mediators that play an important role in the etiology of many inflammatory and autoimmune diseases. This pathway is constitutively activated in various inflammatory conditions and pharmacological inhibition or genetic inactivation of PI3K delta has demonstrated efficacy in several preclinical models of inflammation. GS-1101, a selective inhibitor of PI3K delta, has been evaluated in a Phase 1 study in patients with allergic rhinitis. This talk will discuss the potential utility of PI3K delta inhibitors for the treatment of a variety of inflammatory diseases and present Phase I clinical data in allergic rhinitis.

Identifying and Designing Selective Inhibitors

2:30 Structure Guided Design of Isoform Selective pI3KaI inhbitorsTimothy Heffron, Ph.D., Senior Scientist, Genentech

3:00 refreshment Break in the exhibit Hall with poster Viewing

3:40 Discovery of pF-384: a Clinical pI3K/mtOr Inhibitor Christoph M. Dehnhardt, Ph.D., Senior Principal Scientist, Pfizer The phosphoinositol 3-kinase (PI3K) signaling pathway plays an important role in mitogenic signaling, cell survival, cell growth, proliferation, and metabolic control. Our presentation describes the discovery of PF-384 a pan PI3K (class I)/mTOR inhibitor which has shown compelling efficacy in multiple human tumor nude mouse xenograft models when administered as single agent. The design of this novel potent inhibitor, synthesis, SAR, PK and in vivo efficacy data will be presented.

4:10 talk title to be announcedAdrian L. Smith, Ph.D., Scientist, Amgen

11 | Discovery On Target

Conference DiscountspreSent a pOSter anD SaVe $50!Poster abstracts are due by august 24, 2012. Once your registration has been fully processed, we will send an email containing a unique link allowing you to submit your poster abstract. *CHI reserves the right to publish your poster title and abstract in various marketing materials and products.

reGISter 3 - 4th IS Free: Individuals must register for the same conference or conference combination and submit completed registration form together for discount to apply.alumni Discounts (SAVE 20%)

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4:40 novel, Selective Compound for Leukemia treatmentNikolaus S. Trede, M.D., Ph.D., Associate Professor of Pediatrics, Investigator, The Huntsman Cancer Institute, University of UtahIn a novel approach to identify molecules with activity against hematopoietic malignanciesusing transgenic zebrafish, we discovered Lenaldekar (LDK) that selectively kills primary patient leukemias. We have identified two activities of LDK: members of the PI3K/AKT/mTOR axis (P/A/mT) are inhibited and LDK sensitive cells are delayed in late mitosis. LDK is orally available in mice and, as in live zebrafish, has no recognizable toxicities, making it an attractive molecule for development into a clinically useful therapy.

5:10 Close of Conference

Hotel & Travel Information

conference Venue and Host Hotel: Boston Marriott Copley Place110 Huntington Ave.Boston, MA 02116Tel: 617-236-5800

room rate: $269 s/dreservation cutoff: September 4, 2012

Please visit our conference website to make your reservations online or call the hotel directly to reserve your sleeping accommodations. You will need to identify yourself as a Cambridge Healthtech Institute conference attendee to receive the discounted room rate with the host hotel.

Reservations made after the cut-off date or after the group room block has been filled (whichever comes first) will be accepted on a space- and rate-availability basis. Rooms are limited, so please book early.

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aDDItIOnaL reGIStratIOn DetaILS

Each registration includes all conference sessions, posters and exhibits, food functions, and access to the conference proceedings link.

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to view our Substitutions/Cancellations policy, go to http://www.healthtech.com/regdetails

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Sunday, September 30 tuesday, October 2

An Understanding of Structure- and Fragment- Based Drug Discovery: Tools and Techniques (SC1)

Setting Up Effective RNAi Screens: Getting from Design to Data (SC5)

Pre-Clinical Toxicity (SC2) DINNER SHORT COURSE: Allosteric Modulators (SC6)

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October 1-2, 2012 October 2-3, 2012

1 GPCR-Based Drug Discovery 6 Allosteric Modulators

2 Novel Strategies for Kinase Inhibitors 7 Advances in Targeting the PI3K Pathway

3 Targeting The Ubiquitin Pathway 8 Functional Genomics Screening Strategies

4 Next-Generation Histone Deacetylase Inhibitors 9 Targeting Histone Methyltransferases and Demethylases

5 Targeting Cancer Cell Metabolism 10 Diabetes Drug Discovery and Beyond

DiscoveryOnTarget.com | 12

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3rd Annual | October 2-3, 2012

Advances in Targeting the PI3K Pathway

Inaugural | October 1-2, 2012

Targeting the Ubiquitin Pathway

6th Annual | October 1-2, 2012

Novel Strategies for Kinase Inhibitors

Exploring Signaling Pathways