Cambridge Healthtech Institute’s 9th Annual

Inflammation and Autoimmune Inhibitors

Small-Molecule Approaches for Oral-Based Therapeutics

April 3-4, 2018 | Hilton Bayfront | San Diego, California

Disorders of the immune system, such as chronic inflammation and autoimmune diseases, are increasingly becoming a focus of the drug development industry. Not only is the number of patients with these conditions growing, but possibilities of developing oral-based medicines, which provide more patient convenience for longer-term treatment than current biologic or protein-based injectable treatments, are within reach. A few years ago, the first oral-based treatment for rheumatoid arthritis, a small molecule JAK kinase inhibitor, was launched. Another driver towards developing cell-penetrable chemical agents in the immunology space is the explosion of knowledge of immunological pathways and intracellular disease-causing culprits – which are more numerous than the number of cell surface proteins that biologics are limited to targeting. This conference convenes discovery biologists and chemists who focus in immunology, to hear and provide updates on clinical candidates, discuss medicinal chemistry efforts on new small molecule drug agents and reveal early-stage promising intracellular immunological/inflammation-related drug targets.

Final Agenda

Tuesday, April 3

7:00 am Registration and Morning Coffee

TARGETING INTRACELLULAR KINASES FOR AUTOIMMUNITY AND INFLAMMATION

8:00 Welcome Remarks
Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks

John Robinson, PhD, Director, Medicinal Chemistry, Array Biopharma

8:10 BTK for Lupus and Other Indications: Lead Optimization of a Covalent Inhibitor

Lesley M. Liu-Bujalski, PhD, Group Leader, Medicinal Chemistry, EMD Serono Research and Development Institute, Inc.

Bruton's tyrosine kinase (Btk) is a promising drug target for the treatment of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). We set out to identify an orally bioavailable, highly selective BTK inhibitor, that might be suitable for the treatment of chronic diseases. Using a combination of X-ray crystallography, wild-type and mutant BTK functional assays, stability studies, and in vivo PK/PD models, lead optimization efforts led to the identification of evobrutinib.

8:40 Discovery and Optimization of Spleen Tyrosine Kinase Inhibitors for Immunological Diseases

Michael Hoemann, PhD, Senior Scientist, Department of Chemistry, AbbVie, Inc.

This talk will focus on the approach to designing and optimizing a series of Spleen Tyrosine Kinase (Syk) inhibitors. We will highlight the methods used to enhance potency, overcome the challenge of off-target kinase selectivity and optimization of PK properties to yield compounds with in vivo efficacy in the rat CIA model. In addition, the talk will highlight the use of in vitro assays to identify compounds with superior cardiovascular safety profiles.

9:10 Late Breaking Presentation

9:40 Coffee Break

TARGETING INTRACELLULAR KINASES AND GPCRs FOR AUTOIMMUNITY AND INFLAMMATION

10:05 Discovery of Potent and Selective Inhibitors of Receptor-Interacting Protein Kinase 1 (RIPK1) with in vivo Activity

Snahel Patel, PhD, Senior Scientific Manager, Discovery Chemistry, Genentech, Inc.

Regulation of cell death signaling is critical for the maintenance of homeostasis and prevention of disease. A caspase-independent regulated form of cell death called necroptosis is rapidly emerging as an important mediator of a number of human pathologies including inflammatory bowel disease and ischemia reperfusion organ injury. Activation of necroptotic signaling through TNF signaling or organ injury leads to the activation of kinases RIPK1 and RIPK3 and culminates in inflammatory cell death. Here we present the interesting development of potent and selective RIPK1 specific inhibitors that demonstrate protection in a mouse systemic inflammatory response syndrome (SIRS) model.

10:35 Modulation of Heterotrimeric G proteins by AMP-Kinase: An actionable target in Inflammatory Bowel Disease

Pradipta Ghosh, MD, Professor, Departments of Medicine and Cell and Molecular Medicine, UC San Diego

The gut barrier is a final frontier where trillions of bacteria face-off the largest immune system of the body; a compromised “leaky” gut barrier is frequently associated with chronic inflammation, which is a key initiator and driver for many autoimmune diseases, such as inflammatory bowel disease (IBD). Using normal and IBD-afflicted human enteroids and enteroid-derived monolayers we have revealed an actionable target (AMPK) within a specialized pathway, the stress-polarity signaling pathway, whose activation appears to mend the leaky gut in IBD.

11:05 Ozanimod (RPC1063), an oral S1P1 and S1P5 modulator, in Relapsing Multiple Sclerosis

Kristen Taylor Meadows, PhD, Principal Scientist, Cell and Molecular Biology, Celgene

Ozanimod, a small molecule S1P1 and S1P5 agonist, demonstrated positive Phase III efficacy with a good safety profile in Relapsing Multiple Sclerosis, an autoimmune disorder targeting myelin within the central nervous system. Ozanimod’s primary mechanism of action is to retain lymphocytes in secondary lymphoid tissue. This talk will present data identifying specific peripheral immune populations targeted by ozanimod in preclinical models of MS, and investigate direct effects on resident cells within the central nervous system.

11:35 Enjoy Lunch on Your Own

12:20 pm Session Break

NEW INFLAMMATION AND AUTOIMMUNITY TARGETS

1:15 Chairperson’s Remarks

Lesley M. Liu-Bujalski, PhD, Group Leader, Medicinal Chemistry, EMD Serono Research and Development Institute, Inc.

1:20 Inhibition of the Serine Hydrolase Monoacylglycerol Lipase (MGLL) for the Treatment of Neurological and Neuroinflammatory Disorders

Jacqueline Blankman, PhD, Director of Biology, Abide Therapeutics

ABX-1431 is a first-in-class, small molecule inhibitor of monoacylglycerol lipase (MGLL), a serine hydrolase enzyme that regulates flux of the endocannabinoid 2-arachidonoylglycerol (2-AG). Oral administration of ABX-1431 results in potent and selective MGLL inhibition in preclinical species and man. In an exploratory Phase 1b study in Tourette Syndrome (TS), ABX-1431 administration consistently showed benefit on TS symptoms, supporting MGLL inhibition as a novel CNS mechanism for the treatment of TS and other neurological diseases.

1:50 Late Breaking Presentation:The Role of IL-17 Signaling in NASH- and ASH-induced Liver Fibrosis

Tatiana Kisseleva, MD, PhD., Associate Professor, Department of Surgery, University of California San Diego

2:20 The Design of Mechanism-Based Amine Oxidase Inhibitors for the Treatment of Inflammation

Jonathan Foot, PhD, Senior Research Scientist, Drug Discovery, Pharmaxis Ltd.

Amine oxidases are a family of enzymes that catalyze the oxidation of a wide variety of endogenous amines such as collagen or dopamine. They play a key role in oxidative stress, inflammation and protein cross-linking, and in the initiation and progression of fibrosis and cancer. Herein we will present strategies and chemical routes to identify selective amine oxidase inhibitors for the treatment of inflammation-driven diseases.

2:50 Targeting Lipid Mediator, Hepoxilin, for Combatting Inflammation and Inflammatory Bowel Disease

Cecil Robert Pace-Asciak, PhD, Professor, Translational Medicine and Pharmacology, Hospital for Sick Children Research Institute

Findings related to inflammation will be presented for a family of small molecules, Hepoxilins (HX), originally isolated in my laboratory, and of structural analogs (PBTs) that antagonize HX actions in vivo. Results for lung fibrosis and inflammatory bowel disease and enhanced neutrophil migration will be presented and stimulation of neutrophil extracellular trap formation (NETosis). Other promising biological actions will be discussed. It is hoped that interest in this area will allow clinical development.

3:20 Selected Poster Presentations

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

4:30 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

4:35 Sponsored Plenary Keynote Introduction (Opportunity Available)

4:40 PLENARY KEYNOTE: Activity-Based Proteomics: Protein and Ligand Discovery on a Global Scale

Benjamin F. Cravatt, PhD, Professor and Co-Chair, Department of Molecular Medicine, The Scripps Research Institute
To address uncharacterized proteins, we have introduced chemical proteomic technologies that globally profile the functional state of proteins in native biological systems. Among these methods is activity-based protein profiling (ABPP), which utilizes chemical probes to map activity states of large numbers of proteins in parallel. I will discuss the application of ABPP to discover and functionally annotate proteins in mammalian physiology and disease, and the generation and implementation of advanced ABPP platforms for proteome-wide ligand discovery.

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

6:30 End of Day

Wednesday, April 4

7:30 am Continental Breakfast Breakout Discussions

TARGETING THE IL17 PATHWAY VIA ROR NUCLEAR HORMONE RECEPTORS

8:30 Chairperson’s Remarks

Bryan Laffitte, PhD, Director, Discovery Pharmacology, Genomics Institute of the Novartis Research Foundation

8:35 FEATURED PRESENTATION: RORC2 Inverse Agonists – Finding Lipophilic Efficiency in a Hydrophobic Pocket

Mark Schnute, PhD, Associate Research Fellow, Medicine Design, Inflammation & Immunology Research, Pfizer
Small molecule, inverse agonists of the nuclear hormone receptor RORC2 are potential therapies for several autoimmune diseases through their ability to inhibit pro-inflammatory cytokine production. This presentation will describe how we have used the key design strategies of optimization of lipophilic efficiency and understanding the interplay of structure, pharmacology and target residence time to advance a high-throughput screening hit into a highly potent, selective and orally bioavailable preclinical development candidate.

9:05 Investigation of Thiazole Bis-Amides as RORγt Inverse Agonists

Kelly McClure, Senior Scientist, Immunology Chemistry, Janssen Research & Development

The nuclear transcription factor retinoic acid receptor-related orphan receptor gt (RORgt) drives Th17 cell differentiation and expansion, and cytokine production. Blocking the production of pro-inflammatory cytokines by RORgt modulation has the potential to be an effective treatment for autoimmune diseases. A promising series of thiazole bis-amide RORgt inverse agonists has been identified and our optimization efforts will be discussed.

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

10:30 Targeting of RORγ

Daniel J. Cua, PhD, Group Leader, IMR Pathway Biology, Merck Research Laboratories, Palo Alto
I will present our work demonstrating that targeting of RORgamma restrains TCR gene rearrangement and limits development of auto-reactive T cells.

11:00 The Discovery of AZD0284, an Inverse Agonist of Nuclear Receptor RORγt for the Treatment of Psoriasis

Frank Narjes, PhD, Senior Principal Scientist, Medicinal Chemistry, IMED Respiratory, Inflammation & Autoimmunity, AstraZeneca

Retinoic acid receptor-related orphan receptor C2 (RORc2, RORγt, or NR1F3) is essential for the development and differentiation of IL-17 producing TH17 cells, which are important drivers of chronic inflammation in autoimmune diseases such as psoriasis or ankylosing spondylitis. We describe the discovery of our clinical candidate AZD0284, a compound that combines good oral bioavailability with potent suppression of IL-17 production in human TH17 cells, and is currently in Phase I clinical trials.

11:30 Low Molecular Weight Modulators of RORγ: Efficacy in Autoimmune Disease Models
James Zapf, PhD, CSO and Chris Buhr, PhD, VP Medicinal Chemistry, Visionary Pharmaceuticals

12:00 pm End of Conference