6th Annual

Inflammation Inhibitors

Small Molecule and Macrocyclic Approaches

April 21-22, 2015  


This conference features medicinal chemistry-focused case studies of small molecule and macrocyclic drug candidates progressing in pre-clinical and clinical development. In addition to presentations highlighting the well-known kinase inhibitors progressing in the pipeline, drug leads directed against ‘newer’ kinases and non-kinase targets will be a part of the meeting. Connections between inflammation and other disease processes will also be explored. Join fellow drug discovery scientists for this day-and-a-half meeting that is in the first half of CHI's larger Drug Discovery Chemistry event.

Speakers were great and presented valuable data. Comprehensive conference and
overview of most current inflammation targets and therapies.

Tina T., Associate Scientist, Biogen Idec

Tuesday, April 21

7:00 am Registration and Morning Coffee


8:00 Chairperson’s Opening Remarks

Seng-Lai “Thomas” Tan, Ph.D., Director and Head, Cellular and Translational Immunology, EMD Serono Research and Development Institute, Inc.

8:10 PI3K delta Inhibitors for the Treatment of SLE 

Kamal PuriKamal Puri, Ph.D., Associate Director, Research, Gilead Sciences, Inc.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease generated and maintained by autoreactive T and B cells. PI3Kdelta controls many essential B and T cell functions its activity is enhanced in SLE patient lymphocytes. Emerging preclinical data suggests therapeutic potential of PI3Kdelta inhibitors in SLE. In MRL/lprmice, PI3Kdelta inhibition ameliorated lupus progression, reduced the excessive numbers of T effector cells and B cells, decreased cytokine levels and the number of macrophages infiltrating the kidney.

8:40 Targeting Protein Tyrosine Phosphatase Sigma for Rheumatoid Arthritis Therapy 

 Nunzio BottiniNunzio Bottini, M.D., Ph.D., Associate Professor, Division of Cell Biology, La Jolla Institute for Allergy and Immunology

In the most common form of autoimmune arthritis, rheumatoid arthritis, joints are invaded and destroyed by an inflammatory tissue called pannus- which is composed of immune cells, synoviocytes and neoformed blood vessels. Synovial fibroblasts -a type of synoviocyte that normally lines the inner part of the joint- are a major pannus component and invade and destroy cartilage and bone in rheumatoid arthritis. Elucidation of arthritis-relevant intracellular signaling pathways in synovial fibroblasts is necessary in order to identify targets for novel therapeutic interventions for rheumatoid arthritis patients. This talk will be focused on control of synovial fibroblast signaling by tyrosine phosphatases. In particular we will discuss the role of PTPRS, a tyrosine phosphatase that is regulated by the interaction of its extracellular domain with proteoglycans –an abundant component of joint extracellular matrix and the synovial fluid. We will show that PTPRS regulates synovial fibroblast invasiveness through a mechanism that can be harnessed therapeutically for development of novel anti-rheumatic approaches.

9:10 Phenotyping Blood Polypharmacology via Eicosanoid Profiling of Blood

Jiao Song, Ph.D., Scientist, Discovery Sciences, Janssen R&D

An effective approach to explore drug pharmacology is to profile metabolic changes in response to pharmacological stimuli. We have developed a molecular phenotyping platform by monitoring eicosanoids, the bioactive lipids involved in inflammation and immune modulations, to take “snapshots” of the key metabolic pathways. Our results demonstrated that distinct responses arise from different compounds with the same nominal protein target, allowing visualization of global pharmacology of drugs/individuals with unprecedented resolution, including on- and off-target effects.

9:40 Coffee Break

10:05 Targeting Interferon Regulatory Factor 5 (IRF5) with Cell Penetrating Peptides: Structure-Based Design and Characterization of Novel Tools for Direct Assessment of IRF5 Function

Seng-Lai “Thomas” TanSeng-Lai “Thomas” Tan, Ph.D., Director and Head, Cellular and Translational Immunology, EMD Serono Research and Development Institute, Inc.

Interferon regulatory factor 5 (IRF5) is a critical downstream effector of Toll-like receptor (TLR)-dependent signaling. We report the identification and evaluation of six cell-penetrating peptides (CPPs) designed to disrupt protein-protein interactions considered critical to IRF5 dimerization and/or function. Biochemical studies showed these peptides directly bind IRF5. IRF5 CPPs blocked pro-inflammatory cytokine production in human peripheral blood mononuclear cells stimulated with TLR 7/8 ligand, and IFNa production from plasmacytoid dendritic cells stimulated with TLR9 ligand. Thus, our IRF5 CPPs represent promising tools to probe IRF5 function in vitro and for further development of novel therapeutics against TLR7/8/9-dependent autoimmune diseases.

10:35 Nonimmunosuppressive Cyclophilin Inhibitors as Antiviral and Cytoprotective Agents: the Discovery of Cyclosporines with Improved Pharmaceutical Properties

Jiping FuJiping Fu, Ph.D., Senior Investigator III, Medicinal Chemistry, Novarti

Chemical modification of the cyclosporine scaffold has led to the discovery of non-immunosuppressive analogs that have potential utility for treating diverse viral infections, inflammatory diseases and mitochondrial disorders. We have prepared new non-immunosuppressive cyclosporine analogs with excellent pharmaceutical and pharmacokinetic properties. This talk will describe the chemical biology of non-immunosuppressive cyclophilin inhibitors, details of our lead optimization effort, and the preclinical profile of the clinical candidate NIM258 for treating HCV infection.

11:05 Novel Small Molecule Immunomodulators that Target Toll-Like Receptors 

Hang Hubert YinHang Hubert YinHang Hubert Yin, Ph.D., Associate Professor, Chemistry and Biochemistry & BioFrontiers Institute, University of Colorado

We have developed a novel in silico screening technology, which we applied to target the TLR4/MD-2 complex aiming to identify novel pain management therapy. Experimental results demonstrated that the identified compounds selectively block TLR4 activation both in vitro and in vivo. To demonstrate the general applicability of this methodology, we further developed small-molecule competitive inhibitors of TLRs. 

11:35 Lunch on Your Own

12:05 pm Session Break


1:15 Chairperson’s Remarks

Christopher Smith, Ph.D., Director, Medicinal Chemistry, Takeda

1:20 Identification of RORc Inverse Agonists with Favorable in vivo PK and in vivo Suppression of IL-17

Benjamin FauberBenjamin Fauber, Ph.D., Scientist, Small Molecule Drug Discovery, Genentech

RORc is a promising target for the treatment of inflammatory disease. Signaling through RORc is critical to the differentiation of pro-inflammatory interleukin-17A+ T helper cells. We identified potent and selective RORc inverse agonists using structure-based drug design principles. Compounds in this series displayed favorable in vivo PK properties and modulated IL-17 in a dose-dependent manner during single dose PK/PD experiments. The improved compounds also possessed appreciable selectivity for RORc over other nuclear receptors.


1:50 Discovery of Novel RORγ γinverse Agonists for Targeting TH17 Pathway

Jianhua ChaoJianhua Chao, Ph.D., Associate Director, Medicinal Chemistry, Biogen Idec

RORγt is a ligand-regulated transcription factor and is required for the development and function of multiple important pro-inflammatory lymphocyte lineages including TH17 cells. RORγt-expressing cells and the cytokines they produce have been implicated in the pathogenesis of many autoimmune diseases. Disruption of the RORγt /TH17 pathway by small molecule inhibition may provide useful therapeutic intervention. We have explored multiple series of inverse agonists, achieving potent inhibition of the target and with associated acceptable properties for further investigation.


2:20 Animal Models of Ocular Inflammation and Their Translatability to the Clinic

Gelfman_ClaireClaire M. Gelfman, Ph.D., Senior Director, Preclinical and Translational Services, Ophthalmology, Ora, Inc.

Achieving proof-of-concept in animal models of ophthalmic disease is a commonly desired prerequisite for advancing drugs into the clinic. The decision of the best model for evaluation depends on the disease indication under consideration, as well as the mechanism of action targeted by the therapeutic being tested. In addition, the choice of endpoints for the preclinical studies should mirror, when possible, those that will be evaluated in the clinic. In this presentation, we will review several ocular inflammatory models that recapitulate specific features of ophthalmic disease. Representative data will be presented, as well as validation with clinical comparators, when available. This approach can be applied to the early evaluation of new chemical entities, as well as repurposing of compounds validated in other disease indications. The accumulation of relevant animal model proof of concept data will give leverage to a program and play a critical role in making sound go/no-go decisions early in the development process.

2:35 Refreshment Break in the Exhibit Hall with Poster Viewing

New Targets, New Approaches?

3:20 FEATURED PRESENTATION: Site-Directed Ligand Discovery for PPI and Allosteric Enzymes

Michelle ArkinMichelle Arkin, Ph.D., Associate Professor, Pharmaceutical Chemistry, University of California, San Francisco

Protein-protein interactions and allosterically regulated enzymes have been challenging but important targets for probe- and drug discovery, especially in the inflammation field. We and others have found that fragment-based lead discovery can provide chemical starting points and furthermore serve as insightful probes of protein conformation. The Tethering method of fragment discovery links thiol-containing compounds to specific cysteine residues and therefore serves as a site-directed approach to interrogating ‘cryptic’ allosteric sites and protein interfaces.

3:50 FEATURED PRESENTATION: Allosteric Inhibitors of Interleukin-2-inducible T-cell Kinase (ITK)

Ravi G. Kurumbail, Ph.D., Research Fellow and Structural Biology Laboratory Head, Pfizer

Interleukin-2-inducible T-cell kinase (ITK) is a critical mediator of T cell signaling and hence an attractive target for T-cell mediated inflammatory diseases. We have discovered allosteric Type III inhibitors of ITK that also bind to its ATP site. Through classical medicinal chemistry approaches, we have been successful in further optimization of these compounds that leads to selective inhibition of the inactive form of ITK. We will describe how an integrated biophysical technology platform coupled with classical enzymology studies enabled the discovery of allosteric ITK inhibitors.

4:20 Session Break


4:30 Plenary Keynote Introduction

Gregg Siegal, Ph.D., CEO, ZoBio


Chemotype Coverage in Fragment, Phenotypic, & Deorphanization Screens

Brian K. ShoichetBrian K. Shoichet, Ph.D., Professor, Department of Pharmaceutical Chemistry, University of California, San Francisco

The numbing size of chemical space shouldn’t prevent us from asking what screening libraries are missing relative to what we know to be biologically relevant. I explore the impact of chemotype representation on inhibitor discovery, fragment-based screens, whole organism phenotypic screens, and screens to deorphanize enzymes and GPCRs. Each case is framed by rough calculation and illustrated by specific experimental results. The libraries that result differ as much as the goals of the screen, but specific limits and optimization strategies emerge.

5:30 Welcome Reception in the Exhibit Hall with Poster Viewing


Wednesday, April 22

7:30 am Continental Breakfast Breakout Discussions

In this session, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers. Check our website in February to see the full listing of breakout topics and moderators.

Topic: Phenotypic screening and target-based approaches: what have we learnt?

Moderator: Jörg Eder, Ph.D., Executive Director, Novartis Institutes for BioMedical Research

  • How to select the best approach and what are the success factors?
  • What is the best way to follow-up a phenotypic screen: target-or chemocentric?
  • How to tailor compound screening (sub)collections for the different approaches?

Topic: What can medicinal chemists do better to discover safe and effective anti-inflammatory therapeutics?

Moderator: Christopher R Smith, Ph.D. Director, ChemistryTakeda California

  • Next generation kinase inhibitors – opportunities and challenges
  • Irreversible versus reversible inhibitors. Will irreversible inhibitors drive a boost in approvals?
  • COPD; inhaled versus oral therapies – opportunities and challenges

Topic: Developing kinase inhibitors for chronic indications

Moderator: Kamal Puri, Ph.D., Associate Director, Research, Gilead Sciences, Inc.

  • Utility of kinase selectivity profiling data
  • Safety assessment as an experiment rather than a progression gateway
  • Integrating PK/PD to predict safety margins


8:40 Chairperson’s Remarks

Jianhua Chao, Ph.D., Associate Director, Medicinal Chemistry, Biogen Idec

8:45 Discovery and Design of BTK Inhibitors

Longcheng Wang, Ph.D., Scientist III, Medicinal Chemistry, Pharmacyclics

Pharmacyclics’ ibrutinib (PCI-32765) is a first-in-class small molecule inhibitor for Bruton’s tyrosine kinase (BTK) under Phase III clinical development for B cell malignancies. It binds covalently to Cys481 of BTK and suppresses B cell receptor (BCR) activation of primary B lymphocytes. Ibrutinib’s discovery and some of our recent work for identifying a backup covalent inhibitor for BTK will be discussed.

9:15 Development of a Bruton’s Tyrosine Kinase Inhibitor, ONO-4059: Potential Treatment for Rheumatoid Arthritis & Systemic Lupus Erythematosus

Yuko Ariza, Ph.D., Associate Project Leader, Exploratory Research Laboratories II, Ono Pharmaceutical Co.

ONO-4059 is a highly selective, orally bioavailable inhibitor of Btk and Tec kinase activity with a potency (IC50) of 2.2 and 5.3 nM. Data from the ongoing Phase 1 study in hematology cancer demonstrated a promising efficacy in CLL and NHL with a favorable safety profile. Because ONO-4059 reversibly blocks BCR signaling in B-cells and function in monocyte, mast cell and osteoclasts, we hypothesized that ONO-4059 could be an effective therapy in RA and SLE.

9:45 Coffee Break in the Exhibit Hall with Poster Viewing

10:30 Discovery of a New Series of Small Molecule Bruton’s Tyrosine Kinase Inhibitors

Mark Sabat, Ph.D., Principal Scientist, Medicinal Chemistry, Takeda

Bruton’s Tyrosine Kinase (BTK) is a cytoplasmic tyrosine kinase that regulates immunoreceptor signaling pathways. Inhibition of BTK is postulated to be an efficacious therapy for multiple autoimmune diseases. BTK has a high structural similarity with the kinase LCK with only two residue differences present in the active site. This talk will explain how structural differences between BTK and LCK were exploited to discover a series of highly selective fragment derived candidate molecules.

11:00 PPIP5K 1 and 2: A New Class of Small Molecule Kinases for Anti-Inflammatory Drug Development

Huanchen WangHuanchen Wang, Ph.D., Senior Scientist, Signal Transduction, National Institute of Environmental Health Sciences, NIH

PIP5K1/2 are two small molecule kinases that synthesize 1-IP7, an activator of virus-mediated, interferon-beta transcription. When this inflammatory signature persists, it can predispose humans to obesity, diabetes and age-related cognitive decline. PPIP5Ks therefore offer a new anti-inflammatory target. Structural and mutagenic studies have revealed PPIP5Ks utilize a surface-mounted, substrate-capture site that delivers substrate into the catalytic pocket. This “catch-and-pass” reaction mechanism offers a novel means for pharmacological targeting of this enzyme activity.

11:30 TYK2 Inhibitors and Their Role in IL12- and IL23-Pathway Signaling

Steven MagnusonSteven Magnuson, Ph.D., Associate Director, Discovery Chemistry, Genentech, Inc.

TYK2 is a member of the family of Janus kinases that are receptor-associated cytoplasmic tyrosine kinases with a central role in cytokine signaling. TYK2 is known to be a key mediator of IL12-and IL23-signaling, thus being implicated in diseases of chronic inflammation. Structure- and property-based optimization of screening hits to highly potent and selective TYK2 inhibitors suitable for in vivo studies will be described.

12:00 pm Close of Track