Next-Gen Kinase Inhibitors

healthtech.com/KIN

June 17-19, 2013 | The Revere Hotel | Boston, MA

Cambridge Healthtech Institute’s Eleventh Annual

Organized by: Cambridge Healthtech Institute

Moving Towards a Successful Pipeline

Register by May 10 & Save up to $200!

TOPIC HIGHLIGHTS:

• Non-Cancer Indications

• Designing Selective Inhibitors

• Property-Based Design

• Overcoming Resistance

• Structure-Based Design

• Screening and Validation

Co-LoCated with:

13th Annual Structure-Based Drug Design ConferenceGenome to drug Lead with Big data approach

June 19-21 | healthtech.com/SBd

Final Agenda

SHORT COuRSe:The Art and Science of Kinases*Monday, June 17Course Instructors: Kent D. Stewart, Ph.D., Research Fellow, Structural Biology, AbbvieMaricel Torrent, Ph.D., Senior Scientist III, Molecular Modeling, AbbVie*Separate Registration Required.

Corporate Sponsors

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This established and well-recognized kinase conference addresses reoccurring questions about selectivity, safety, resistance and novelty. After many years of research and therapeutic developments of kinase inhibitors, the field still offers new opportunities as novel kinases and their inhibitors are making an appearance. In addition, interest in repurposing of already developed drugs is growing immensely.

“Next-Gen Kinase Inhibitors” addresses what lies ahead, what is in store for the pharmaceutical industry and what new avenues are opening up in regards to technologies and methods used, and in regards to novel targets and therapeutic approaches explored.

Monday, June 17

8:00 – 9:00 am Pre-Conference Short Course Registration and Morning Coffee

9:00 – 12:00 pm Short Course: The art and Science of Kinases*Course Instructors: Kent D. Stewart, Ph.D., Research Fellow, Structural Biology, AbbvieMaricel Torrent, Ph.D., Senior Scientist III, Molecular Modeling, AbbVie

*Separate Registration Required

11:00 am Main Conference Registration

1:30 pm Chairperson’s opening RemarksGuido Zaman, Ph.D., Founder, Head, Biology, Netherlands Translational Research Center B.V.

non-Cancer Indications1:40 The design and optimization of Selective Protein Kinase C theta (PKCθ) Inhibitors for the Treatment of autoimmune diseasesJuan-Miguel Jimenez, Ph.D., Director, Chemistry, Vertex Pharmaceuticals (Europe) Ltd.Protein kinase C theta (PKCθ) has a central role in T cell activation and survival. Studies in PKCθ-deficient mice have demonstrated that whilst anti-viral responses are PKCθ-independent, T cell responses associated with autoimmune diseases are PKCθ- dependent. Thus, potent and selective inhibition of PKCθ is expected to block autoimmune T cell responses without compromising antiviral immunity. The presentation will describe the design and optimisation of a novel class of potent and selective PKCθ inhibitors, which show exceptional potency in cells and in vivo.

2:10 JaK Inhibition Suppresses osteoclast activation through decreased RanKL ProductionTimothy P. LaBranche, DVM, Ph.D., Dipl ACVP, Senior Principal Scientist, Pathologist, Pfizer Drug Safety R&D, Cambridge, MAPotent inhibition of human T lymphocyte RANKL production by the JAK inhibitor tofacitinib (Xeljanz), combined with the lack of an effect on human osteoclast differentiation/function suggests that JAK inhibition suppresses osteoclast-mediated bone resorption through decreased RANKL production. Although T lymphocytes clearly appear to play a role in osteoclast activation by producing RANKL, it is possible that they do not represent the totality of RANKL production in the arthritic joint.

2:40 Combining Cellular and Biochemical Panel Profiling for the development of Selective Kinase InhibitorsGuido Zaman, Ph.D., Founder, Head, Biology, Netherlands Translational Research Center B.V.The Netherlands Translational Research Center B.V. (NTRC) aids in the development of new personalized therapies for the treatment of cancer, autoimmuneand neurodegenerative diseases. Selective kinase inhibitors are optimized for increased target residence time and profiled on large panels of biochemical and cell-based assays. Genotypic, phenotypic and pathway information are combined to determine the optimal compound for a particular patient responder population. Kinase inhibitors are tested in combination with existing drugs to identify new synergies that improve the efficiency of established therapies

3:10 Refreshment Break in the exhibit Hall with Poster Viewing

3:40 effector Kinase Coupling enables HTS for Inhibitors of HIV-1 accessory Protein FunctionTom Smithgall, Ph.D., William S. McEllroy Professor of Biochemistry; Chairman, Microbiology and Molecular Genetics, University of Pittsburgh School of MedicineNef is an HIV accessory protein that enhances viral infectivity, promotes viral replication, and enables HIV-infected cells to escape host immune

Next-Gen Kinase Inhibitors

Cambridge Healthtech Institute’s Eleventh Annual

Moving Towards a Successful Pipeline

June 17-19, 2013The Revere Hotel | Boston, MA

healthtech.com/KIN Next-Gen Kinase Inhibitors | 3

surveillance. While an attractive target for antiretroviral drug discovery, Nef presents a challenge for direct HTS assay development because it lacks intrinsic enzymatic or biochemical activity. To circumvent this problem, we developed an HTS-compatible assay that couples Nef to the activation of Hck, a Src-family kinase and Nef effector protein. Using this assay, we screened a large, diverse chemical library and identified small molecules that selectively block Nef-dependentHck activity with low micromolar potency. Of these, a diphenylpyrazolo compound demonstrated sub-micromolar potency in HIV-1 replication assays against a broad range of primary Nef variants. This compound binds directly to the Nefprotein and disrupts Nef dimerization in cells as a likely mechanism of action. Coupling of non-enzymatic viral accessory factors to host cell effector proteins amenable to HTS may represent a general strategy for the discovery of new antimicrobial agents.

4:10 Targeting aurora a Kinase to overcome CML acquired ResistanceWenYong Chen, Ph.D., Associate Professor, Department of Cancer Biology, Beckman Research Institute/City of HopeCML develops acquired resistance to tyrosine kinase inhibitors by acquisition of BCR-ABL kinase domain mutations. We found that an early event for emergence of BCR-ABL mutant cells is mitotic crisis of CML cells triggered by tyrosine kinase inhibitor treatment, and it is controlled by mitotic kinase Aurora A. Specific inhibition of Aurora A is able to prevent acquisition of BCR-ABL mutations and block CML cell relapse from tyrosine kinase inhibitors.

4:40 Q&a with afternoon Speakers

5:00 Welcome Reception in the exhibit Hall with Poster Viewing

6:45 Close of day one

TueSday, June 18

7:45 am Breakfast Breakout discussionsThese are moderated discussions with brainstorming and interactive problem solving, allowing conference participants from diverse backgrounds to exchange ideas, experiences, and develop future collaborations around a focused topic.

Table 1: Multi-Parameter drug optimization – Is It Working?• Is data quality good enough?•How many compounds should be made and in what stage?•What is the ideal path for optimization and how do you find

it efficiently?•What role does informatics have? – small companies vs

large companiesModerator: Mark Ashwell, Ph.D., Vice President, Chemistry, ArQule

Table 2: How Can We Leverage existing data on Protein Kinases for Inhibitor design?•Challenges in protein kinase data mining•Resources needed to address data mining challengesModerator: Natarajan Kannan, Ph.D., Assistant Professor, Biochemistry and Molecular Biology; Institute of Bioinformatics, University of Georgia

8:55 Chairperson’s RemarksMark Ashwell, Ph.D., Vice President, Chemistry, ArQule

Property-Based design

9:00 Focusing on the Ligand-Protein Relationship in activation-State dependent Conformational Changes of Protein KinasesMark Ashwell, Ph.D., Vice President, Chemistry, ArQuleThe traditional protein kinase inhibitor design process is being expanded as we learn more about the changing nature of the ATP-binding cleft and its switching between active and inactive states. The presentation will describe the utilization of a new understanding of the role of hydrophobic residues within the cleft and how the ligand-protein interactions influence conformational changes, providing new inhibitor design opportunities.

9:30 adP detection Platform for Kinase Inhibitor Screening and ProfilingHicham Zegzouti, Ph.D., Senior Research Scientist, R&D, Promega CorporationThe ADP-Glo™ kinase assay is a universal and robust assay for determining kinase activity using the universal kinase reaction product ADP as readout. Because of its high sensitivity, we utilized this format to profile 174 kinases covering the various families of the kinome. These enzymes were grouped in multi-well strips containing eight enzymes each, and were optimized for generating an activity within the linear response of the kinase. Here we present the profiling of several kinase inhibitors using these standardized profiling systems. The ADP-Glo™ platform offers tremendous benefits to kinase screening and profiling programs along with the ability to study the mode of action of various inhibitors in an affordable way using one assay format during the various stages of drug discovery.

10:00 Coffee Break in the exhibit Hall with Poster viewing

10:45 Structure and Property Based design of CK2 Kinase InhibitorsJames Dowling, Ph.D., Scientist, AstrazenecaThe serine/threonine protein kinase CK2 regulates cell growth, proliferation and evasion of apoptosis by phosphorylation of a range of substrates in several critical cellular signaling pathways and is an attractive target for drug discovery in oncology. To identify chemical starting points against the target, we screened a kinase-focused subset of the AZ compound collection and applied structure-based approaches to further enrich and diversify the output. Property-based design strategies were integrated to identify series with sufficient enzymatic potency, kinase selectivity and molecular characteristics that would enable us to carry out pharmacodynamic and efficacy studies using an orally administered agent. Agents derived from these approaches modulate pAKTS129, a direct substrate of CK2, in vitro and in vivo, and exhibit tumor growth inhibition when evaluated in disease model studies.

developing Selective Inhibitors11:15 evolutionary and Semantic Web applications in Protein Kinase Inhibitor designNatarajan Kannan, Ph.D., Assistant Professor, Biochemistry and Molecular Biology & Institute of Bioinformatics, University of Georgia, AthensProtein kinases display complex sequence-structure-function relationships, a detailed understanding of which is necessary for the development of selective protein kinase inhibitors. This talk describes how evolutionary- and ontology-based analysis of protein kinase data can provide new insights into sequence-structure-function relationships,

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and aid in the development of selective protein kinase inhibitors.

11:45 Selective Inhibition of Kinase-driven Pathways; exploiting demure FeaturesEllen R. Laird, Ph.D. Research Fellow, Array BioPharmaSelective inhibition of nearly any given protein kinase continues to challenge investigators. Literature reviews generally focus upon gross differences in kinase fold, with emphasis on “inactive” vs. “active” conformations, yet many of these compounds remain stubbornly promiscuous. We have curated and analyzed a sizeable collection of X-ray crystal structures of diverse kinases, many of which are proprietary. We have identified additional sources for selectivity by consideration of nuances at the periphery of active or inactive folds. Differences in sidechain rotamer preferences and solvation, cleft dimension, features of the active site floor, the P-loop, and the C-helix often contribute to hypotheses that enable SAR interpretation and further compound design. This talk will draw upon prominent examples of inhibitors that owe their selectivity to these subtle differences, with particular emphasis on our own experiences with AKT, B-Raf, and Erb-B2.

12:15 pm Luncheon PresentationSpeaker to be Announced

1:35 Chairperson’s RemarksNatarajan Kannan, Ph.D., Assistant Professor, Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia

1:40 Structure-Based design of Selective hSmg-1 Kinase InhibitorsAriamala Gopalsamy Ph.D., Associate Research Fellow, Worldwide Medicinal Chemistry, Pfizer Global Research and DevelopmenthSmg-1 kinase plays a key role in cellular genotoxic stress response and contributes to tumor growth and resistance to chemotherapy. To understand the functional role of inhibiting this underexplored Ser-Thr kinase, we identified pyrimidine-based, highly hSmg-1 selective kinase inhibitors. Use of structure based optimization to achieve selectivity will be discussed in detail.

2:10 Sponsored Presentation (Opportunity Available)

2:40The SyK–BTK axis as a drug Target for autoimmune disordersCheng Liao, Ph.D., Senior Scientist II, EMD Serono Research & Development InstituteSpleen Tyrosine Kinase (SYK) and Bruton’s Tyrosine Kinase (BTK) are non-receptor cytoplasmic tyrosine kinases that are primarily expressed in cells of hematopoietic lineage. Both are key mediators in coupling activated immunoreceptors to downstream signaling events that affect diverse biological functions, from cellular proliferation, differentiation and adhesion to innate and adaptive immune responses. As such, pharmacological inhibitors of SYK or BTK are being actively pursued as potential immunomodulatory agents for the treatment of autoimmune and inflammatory disorders. Here, we review and discuss recent insights into the emerging role of the SYK–BTK axis in innate immune cell functions, and our experience in developing selective SYK and BTK inhibitors.

3:10 Refreshment Break in the exhibit Hall with Poster Viewing

Case Studies4:00 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 tumor types.

4:30 discovery and development of Jakafi for MyelofibrosisKris Vaddi, DVM, Ph.D., Group Vice President, Pharmacology and Toxicology, Incyte PharmaceuticalsJakafi (ruxolitinib) is a potent, selective and first in-class JAK1 and JAK2 inhibitor, approved by USFDA for the treatment of patients with intermediate- and high-risk myelofibrosis. Myelofibrosis is a serious and life-threatening myeloproliferative neoplasm (MPN), but unlike CML is Philadelphia chromosome negative. An important discovery in late 2004 that identified a somatic gain-of-function mutation known as JAK2 V617F in MPN patients provided first molecular and genetic evidence that linked JAK-STAT dysregulation to the pathogenesis of MPNs. Drug discovery program at Incyte aimed at developing JAK inhibitors began in early 2003, almost 2 years ahead of the discovery of JAK2V617F with the recognition that JAK-STAT pathway is an important oncogenic and inflammatory mechanism. This early start allowed Incyte to identify Jakafi in

5:30 Close of day

WedneSday, June 19

7:30 am Morning Coffee

8:25 Chairperson’s RemarksDoriano Fabbro, Ph.D., CSO, Piqur Therapeutics

» KeynoTe PReSenTaTIon8:30 Kinase Inhibitors: Lessons Learned? Doriano Fabbro, Ph.D., CSO, Piqur TherapeuticsOur knowledge on the structural determinants of kinase inhibition by small molecules binding to the ATP pocket has advanced steadily in the past years. We will give an overview on the status quo of kinase inhibition and discuss an example on how protein kinases can be structurally affected by selective kinase inhibitors. In addition we will also discuss on how to target kinases whose cellular signaling pathways are only poorly understood.

Screening and Validation9:00 evaluation of the PI4KIIIα Lipid Kinase as a Hepatitis C Virus drug Target: From Inhibitor Screening to animal ModelsFrederic Vaillancourt, Ph.D., former Senior Research Scientist, Department of Biological Sciences, Research and Development, Boehringer Ingelheim (Canada) Ltd.PI4KIII is an essential host cell factor for HCV replication. Screening, using an in vitro biochemical lipid kinase assay, led to the identification of potent inhibitors. In cell culture studies these inhibitors were used to demonstrate that the kinase activity was essential for HCV RNA

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replication, and a resistance study performed, using two of these inhibitors, provided additional insight into the potential role of PI4KIIIα and its product in the HCV viral life cycle. A comprehensive assessment of PI4KIIIα as a drug target in vivo through conditional transgenic murine lines that mimic target-specific inhibition in adult mice demonstrated an essential host physiologic role for PI4KIIIα.

9:30 Coffee Break

10:00 Fitting Technology to Screening Strategy: a Probe displacement assay to Help Identify novel Protein Kinase InhibitorsRamesh Padmanabha, Ph.D., Principal Scientist, Lead Discovery, Lead Profiling and Compound Management, Bristol-Myers Squibb R&DThe talk will outline assay design process to select the probe displacement assay over standard kinase activity assays. The details of the HTS will also be discussed and will include validation, quality control, and data analysis. The outcome from the screen and selectivity data will also be presented.

10:30 accuracy of docking and Scoring Into KinasesIstvan Enyedy, Ph.D., Senior Scientist, Small Molecule Drug Discovery, Biogen IdecScoring functions cannot predict binding affinity and it is challenging even to distinguish between compounds that differ by more than 100 fold in potency. The talk will evaluate the influence of structure and constraints on the outcome of docking and scoring of compounds into 10 kinases and more than 100 structures. In addition, a comparison of several metrics in estimating the precision of scoring will be presented.

Structure - Based design 11:00 Structure-Based drug design: Redefining Protein-Ligand InteractionsJose Duca, Ph.D., Head, Computer-Aided Drug Discovery, NovartisSince the introduction of the lock and key hypothesis, structure-based drug design has been equivalent to understanding and designing protein-ligand interactions. A novel theory of binding that encompasses protein-ligand interactions will be introduced and exemplified.

11:30 enjoy Lunch on your own

1:15 pm Chairperson’s RemarksAdam C. Palmer, Ph.D., Postdoctoral Fellow, Department of Systems Biology, Harvard Medical School•the special role that structure-based drug design can play in treating

drug resistant infectious disease•how considering the evolution of resistance during drug development

could produce drugs with more long-lasting clinical efficacy•how drug resistance can be used as a tool to understand mechanism

of drug action

1:20 Structure-Based design of Potent and Selective Inhibitors of PI3-Kinase deltaJeremy M. Murray, Ph.D., Scientist, Structural Biology, GenentechInhibition of PI3Kδ is considered to be an attractive mechanism for the treatment of inflammatory diseases and leukocyte malignancies. Using a structure-based design approach, we have identified a series of potent and selective inhibitors of PI3Kδ. These inhibitors do not occupy the induced selectivity pocket between Trp760 and Met752 that is observed for other families of selective PI3Kδ inhibitors. Instead, the selectivity of the compounds for inhibition of PI3Kδ relative to other PI3K isoforms

appears to be due primarily to the strong interactions these inhibitors are able to make with Trp760 in the PI3Kδ binding pocket. This talk will discuss the structural understanding of the selectivity of these inhibitors against other isoforms, pharmacokinetic properties and the ability of select compounds to inhibit the function of B-cells in vivo.

1:50 Md Simulations of Mutant and WT PI3Kα: Insights into the Mechanism of overactivation and Implications for drug designZoe Cournia, Ph.D., Investigator, Biomedical Research Foundation, Academy of AthensUnderstanding how the p110α H1047R mutation causes tumorigenesis is central to developing new therapeutics for cancer. To this end, MD simulations in aqueous solution were carried out for 100 ns for both WT and mutant proteins. Our results indicate that key regions of the protein, such as the catalytic, activation, membrane binding loops and the C-terminus, all exhibit significantly different dynamics in the mutant with respect to the WT protein.

2:20 Guiding the design of Robust Inhibitors Targeting HIV and HCV Proteases by using the dynamic Substrate envelopeAysegul Ozen, Ph.D. Candidate, Biochemistry & Molecular Pharmacology, University of Massachusetts Medical SchoolDrug resistance is a major concern in the treatment of quickly evolving diseases. At the molecular level, drug resistance reflects a subtle change in the balance of molecular recognition by the target enzyme due to mutations in favor of substrate processing versus inhibitor binding. Robust inhibitors can be designed by mimicking the binding features of the natural substrates to minimize the chances of resistance.

2:50 Refreshment Break in the exhibit Hall with Poster Viewing

drug Resistance3:30 Towards a new Generation of antimicrobial antifolatesDennis L. Wright, Ph.D., Professor of Pharmaceutical Sciences and Chemistry, University of ConnecticutWe are using a structure-based design approach to develop potent and selective inhibitors of the enzyme dihydrofolate reductase (DHFR) from a variety of pathogenic organisms. Analysis of crystal structures of trimethoprim-resistant and naturally insensitive enzymes led to the design of a series of propargyl-linked antifolates characterized by high potency, good selectivity over the human form of the enzyme and good anti-microbial activity.

4:00 understanding drug Mechanism of action by Target Gene overexpressionAdam C. Palmer, Ph.D., Postdoctoral Fellow, Department of Systems Biology, Harvard Medical SchoolThe molecular targets of drugs can sometimes, but not always, be identified amongst genes that confer drug resistance when overexpressed. We quantitatively overexpressed genes encoding known antibiotic targets and observed that drug resistance does not only increase; it can remain unchanged, decrease, or even have a non-monotonic dependence on target expression. These diverse effects are explained by simple models considering gene toxicity and drug-induction of harmful target-catalyzed reactions. The relation between drug resistance and target expression may reveal unexpectedly complex mechanisms of drug action.

5:00 Close of Conference

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Hotel & Travel InformationConference Hotel:The Revere Hotel200 Stuart St.Boston, MA 02116Tel: 617-482-1800

Discounted Room Rate: $249 s/dDiscounted Reseveration Cut-off Date: May 17, 2013

Please visit our conference website to make your reservation online or you may call the hotel directly. 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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• Call American Airlines 1-800-433-1790 use Conference code 4463BU.

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