7th Annual

Inflammation Inhibitors

Small Molecule and Macrocyclic Approaches

April 19-20, 2016  

Inflammation Inhibitors icon

This meeting features medicinal chemistry-focused case studies of small molecule drug candidates that are being tested in preclinical and early-phase clinical trials for inflammation-related conditions. Because the most recent ‘market’ successes for oral, anti-inflammatories have been against the intracellular janus kinases (JAKs), updates on progress of new and 2nd generation intra-cellular kinase inhibitor candidates will be covered. But drug leads directed against non-kinase targets such as nuclear receptors involved in innate immunity, will also be a part of the meeting. 

Final Agenda

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Tuesday, April 19

7:00 am Registration and Morning Coffee


8:00 Chairperson’s Opening Remarks

Eric Schwartz, Ph.D., Executive Director, Medicinal Chemistry, Celgene

8:10 FEATURED PRESENTATION: Small Molecule Modulators of RORgamma

Robert HughesRobert Hughes, Ph.D., Senior Associate Director, Small Molecule Discovery Research, Boehringer-Ingelheim

RORγt is a nuclear hormone receptor expressed in Th17 cells and distinct subsets of lymphoid cells, including innate lymphoid cells (ILC), and γδ T-cells. RORγt is required for Th17 cell and innate lymphocyte differentiation and regulates the transcription of the effector cytokines genes such as IL17A. We describe our approach, including screening, structure-based design and optimization, which led to the discovery of potent, selective ROR g modulators with favorable ADME properties.

8:40 Quinoline Tertiary Alcohols as Modulators of Retinoic Acid Receptor-Related Orphan Receptor gamma t (RORγt)

Hari_VenkatesanHari Venkatesan, Ph.D., Principal Scientist, Discovery Chemistry, Immunology, Janssen Research & Development

Differentiation of naïve T-cells into IL-17 producing Th17 cells is regulated by the nuclear receptor transcription factor retinoic acid receptor-related orphan receptor gt (RORgt). Blocking the production of pro-inflammatory cytokines by RORgt modulation has the potential to be a first-in-class treatment of autoimmune diseases. High-throughput screening identified a promising series of quinoline tertiary alcohols. The subsequent optimization efforts that resulted in the identification of compounds for in vivo profiling will be discussed.

9:10 Highly Selective and Cell-potent ASK1 Inhibitors 
Christoph Zapf, Ph.D., Senior Principal Scientist, Worldwide Medicinal Chemistry, Pfizer Research Labs

9:40 Coffee Break

10:05 Inducing RORgamma-Specific Inverse Agonism Using a Synthetic Benzoxazinone Ligand

Doug_MarcotteDoug Marcotte, Associate Scientist, Physical Biochemistry, Biogen

RORγ regulates transcriptional genes involved in production of pro-inflammatory interleukin IL-17 which is linked to autoimmune diseases. We have discovered a series of synthetic benzoxazinone ligands having either an agonist (BIO592) or inverse agonist (BIO399) mode of action. We demonstrate that upon binding of BIO399 the AF2 helix of RORγ become destabilized. The X-ray structures of RORγ with BIO592 and BIO399 demonstrates how small modifications modulate the mode of action for achieving RORγ-specific inverse agonism.

10:35 Small Molecule Inhibitors of RORgamma and IRAK4 for the Treatment of Autoimmune Disorders

Susanta_SamajdarSusanta Samajdar, Ph.D., Director, Medicinal Chemistry, Aurigene Discovery Technologies Limited

Although biologics such as anti-TNFα antibody are fairly successful in the treatment of autoimmune disorders, there is significant unmet need due to heterogeneity in diseases and lack of response to established therapies in some patients. While biologics typically target one cytokine signaling pathway, small molecule therapeutics directed towards intracellular target(s) can interfere in the signaling from multiple cytokines potentially leading to improved response. Development of small molecule oral inhibitors of IRAK4 and RORgamma to target TLR/IL-R and Th17 pathway respectively will be discussed.

11:05 Structure-Based Design of Macrocyclic IL-17A Antagonists

Shenping_LiuShenping Liu, Ph.D., Associate Research Fellow, Structural Biology and Biophysics, Pfizer Global Research and DevelopmentI

IL-17A is a pro-inflammatory cytokine that has been implicated in many autoimmune and inflammatory diseases. Monoclonal antibodies targeting the IL-17A pathway have shown significant efficacies in treating psoriasis and Psoriatic arthritis in late stage clinical trials, and one of them was approved recently. We are interested in developing small molecule IL-17A antagonists for oral medication. We have determined several IL-17A/antagonists complex structures. These structures enabled us to design macrocyclic IL-17A antagonists with much improved potencies.

11:35 Enjoy Lunch on Your Own

12:05 pm Session Break


1:15 Chairperson’s Remarks

Jennifer Venable, Ph.D., Associate Scientific Director, Medicinal Chemistry, J&J

1:20 Discovery of Potent, Selective, and Non-Covalent BTK Inhibitors for Clinical Development

Wendy_YoungWendy B. Young, Ph.D., Vice President, Discovery Chemistry, Genentech

We developed a series of highly potent, selective, non-covalent Btk inhibitors that are efficacious in several rodent models of RA and lupus. Compounds in this chemical series remain highly active against the C481S Btk mutant identified in patients that have relapsed on Imbruvica®. We describe the SAR, preclinical DMPK and toxicology investigations leading up to the discovery and selection of our lead clinical candidate, GDC-0853. Results from our Phase 1 clinical trials will be shared.

1:50 A Covalent BTK Inhibitor for Inflammation

Eric_SchwartzEric Schwartz, Ph.D., Executive Director, Medicinal Chemistry, Celgene

This presentation will discuss the identification and characterization of a covalent BTK inhibitor with in vitro, in vivo and preliminary toxicity data presented.

2:20 BTK and other Case Studies: Fragment Hit Prioritization and Optimization for Immunology Targets

Jason_PickensJason Pickens, Ph.D., Senior Scientist, Medicinal Chemistry, Takeda

As cutting-edge methods for fragment screening evolve into a series of best practices, the question of how to prioritize fragment hit sets to select the “best” fragments for initial chemistry follow-up elicits wide-ranging levels of analysis and opinion among FBDD practitioners. Through select case studies of immunology targets including BTK, this presentation will illuminate some specific strategies employed recently by medicinal chemistry teams at Takeda California in the pursuit of high-quality drug candidates derived from fragment starting points.

2:50 Structure-Activity-Relationships around Lead Series of Selective Jak1 Inhibitors for Inflammation

Michael_VazquezMichael L. Vazquez, Ph.D., Associate Fellow, Medicinal Chemistry, Pfizer, Inc.

Our research efforts have identified a series of potent and selective JAK1 inhibitors. Our lead, PF-04965842, is currently in clinical trials for the treatment of autoimmune diseases. This talk will discuss learnings from our clinical experience with tofacitinib a pan-JAK inhibitor with respect to potency and selectivity, SAR, the preclinical evaluation of our lead, and crystallographic data which has enabled us to build a structural hypothesis for the JAK1 selectivity.

3:20 Selected Poster Presentations

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing


A Chemist's Foray into Translational Research

Peter SchultzPeter G. Schultz, Ph.D., Professor, Department of Chemistry, The Scripps Research Institute and Director, California Institute for Biomedical Research

Our research program combines the tools and principles of chemistry with the molecules and processes of living cells to synthesize new molecules and molecular assemblies with novel physical, chemical and biological functions. By studying the structure and function of the resulting molecules, new insights can be gained into the mechanisms of complex biological and chemical systems.

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

6:30 Close of Day

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Wednesday, April 20

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: Developing Kinase Inhibitors for Chronic Indications

Moderator: Kamal Puri, Ph.D., Senior Principal Scientist, Immunology & Inflammation, Celgene Corp.

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

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

Moderator: Jennifer Venable, Ph.D., Associate Scientific Director, Medicinal Chemistry, J&J

  • Next generation kinase inhibitors – opportunities and challenges
  • Irreversible versus reversible inhibitors. Will irreversible inhibitors drive a boost in approvals?
  • Phenotypic screening

Topic: Targeting Innate Immunity

Moderator: Robert Hughes, Ph.D., Senior Associate Director, Small Molecule Discovery Research, Boehringer-Ingelheim

  • RORg challenges
  • Promising targets in pathway
  • Downstream development issues
  • Animal models


8:30 Chairperson’s Remarks

Kamal Puri, Ph.D., Senior Principal Scientist, Immunology & Inflammation, Celgene Corp. 

8:35 PTG-100: An Oral Peptide Antagonist of α4β7 Integrin for Ulcerative Colitis

Larry_MattheakisLarry Mattheakis, Ph.D., Senior Director, Biology, Protagonist Therapeutics

PTG-100 is an oral peptide antagonist of the gut homing integrin α4β7. Its potency and selectivity are similar to that of the FDA-approved antibody vedolizumab. PTG-100 was chemically engineered to be orally stable within the harsh proteolytic and reducing environment of the human gastrointestinal tract. In preclinical animal models, PTG-100 exposure is largely restricted to GI tissues, whereby it alters the trafficking of gut homing T cells to reduce local inflammation. Together, these results provide the rational for investigating PTG-100 in human trials, specifically ulcerative colitis.

9:05 ATPase Modulators for Treating Inflammatory Bowel Disease

Alexander_HurdAlexander (Sandy) Hurd, Ph.D., Associate Director of Chemistry, Chemistry, Lycera Corp

Autoimmune diseases occur in part as a result of dysregulation of the natural immune response. Autoimmune disease is characterized by chronic activation of lymphocytes that recognize and attack naturally occurring, endogenous targets. These chronically activated lymphocytes exhibit a distinct bioenergetic profile in comparison to acutely activated immune cells, which provide a target for therapeutic intervention. Lycera is developing modulators of the mitochondrial ATPase to treat autoimmune conditions such as inflammatory bowel disease (IBD). The talk will include a description of the identification and characterization of Lycera’s current lead candidate for treating IBD.

9:35 Coffee Break in the Exhibit Hall with Poster Viewing

10:30 AKB-4924: Targeting Hypoxia Inducible Factor 1 for Therapy of Inflammatory Bowel Disease

Kevin_PetersKevin Peters, M.D., CSO and Senior Vice President, R&D, Aerpio Therapeutics, Inc.

Emerging evidence shows that hypoxia inducible factor 1 (HIF-1) is an important regulator of the immune response. AKB-4924 is a novel small molecule inhibitor of HIF prolylhydroxylases (PHDs), a family of enzymes that promotes HIF degradation. AKB-4924 preferentially stabilizes HIF-1 over HIF-2 and has profound beneficial effects in multiple models of inflammatory bowel disease by either parenteral or oral administration without concomitant increases in erythropoiesis. These data support advancement of AKB-4924 into the clinic.

11:00 CHDI-00340246: A Potent and Selective Kynurenine Monooxygenase Inhibitor as a Potential Therapeutic Agent for the Treatment of Huntington’s Disease

Leticia Toledo-Sherman, Ph.D., Director of Medicinal Chemistry, CHDI Foundation

Deregulation of the kynurenine pathway, has been implicated in the pathophysiology of Huntington’s Disease (HD). This talk will describe CHDI’s medicinal chemistry efforts that lead to the identification of CHDI-00340246, a highly potent and selective KMO inhibitor that has been nominated as clinical candidate for the treatment of HD. We will describe the pharmacokinetic/pharmacodynamics effects of CHDI-00340246 in several species, as well as its biological effects in various disease models.

11:30 Towards Third Generation Antihistamines as Potent Inflammation Inhibitors

iwan_de_EschIwan de Esch, Ph.D., Professor, Medicinal Chemistry, VU University Amsterdam & Griffin Discoveries BV

The histamine receptor consists of four subtype GPCRs. The histamine H1 receptor has been successfully targeted by two generations of blockbuster drugs. With the emerging insights into the role of the other histamine receptor subtypes in the different mechanisms of inflammatory responses, there is now a growing interest in poly-pharmacological approaches. We will disclose how fragment-based approaches and computer-aided drug design have resulted in series of compounds with well defined activity profiles for histamine receptor subtypes. These compounds proof potent anti-inflammatory compounds in various preclinical studies.

12:00 pm Close of Track

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