Cambridge Healthtech Institute’s 10th Annual

Inflammation Inhibitors

Medicinal Chemistry for Oral-Based Autoimmune and Inflammation Related Therapeutics

April 10-11, 2019

Efforts to find and develop small molecule-based drug agents for combatting inflammation and autoimmune-related conditions is intensifying in the drug discovery industry. The first oral-based treatment for rheumatoid arthritis, a small molecule JAK kinase inhibitor, was launched a few years ago. The focus on oral-based anti-inflammatory agents (which are mostly small molecules though some macrocyclics and constrained peptides can also penetrate cells) is not only because oral-based therapeutics afford greater patient convenience, but also because of the rapidly accumulating scientific knowledge of the myriad of intracellular molecules involved in inflammation and autoimmune-related conditions. Cambridge Healthtech Institute's 10th annual Inflammation Inhibitors conference convenes discovery chemists and biologists who work on immunology-related drug targets to learn from one another and stay abreast of the latest discovery and medicinal chemistry efforts in the field.

Final Agenda

Wednesday, April 10

12:30 pm Registration Open (20 C/D Foyer)

12:45 Dessert Break in the Exhibit Hall with Poster Viewing

INTRACELLULAR KINASE INHIBITORS (AND MORE) FOR INFLAMMATION AND AUTOIMMUNITY
30 D/E

1:30 Welcome Remarks

Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute

1:35 Chairperson’s Opening Remarks

Phillip Schwartz, PhD, Associate Principal Scientist, Pharmacology, Merck Research Laboratories

1:40 FEATURED PRESENTATION: Discovery of a Cross-Species Potent and Selective Inhibitor of Receptor-Interacting Protein Kinase (RIPK1) Providing Protection in a Number of Immunological Models

Snahel Patel, PhD, Scientist, Discovery Chemistry, Genentech, Inc.

Regulation of cell death signaling is critical for the maintenance of homeostasis and prevention of disease. Necroptosis, a caspase-independent regulated form of cellular death, is emerging as an important mediator of a number of human pathologies. Activation of necroptotic signaling through TNF signaling or organ injury activates RIPK1 and RIPK3 leading to inflammatory cell death. We present the development of a cross-species potent and selective small molecule inhibitor of RIPK1 to explore the prevention of cell death in a number of disease models of inflammation.

2:10 Considerations in the Generation of Covalent BTK Inhibitors

Noel S. Wilson, MSc, Senior Scientist III, Discovery Chemistry and Technology, AbbVie

Bruton tyrosine kinase (BTK) plays a central role in signaling from the B-cell receptor, which has prompted the development of small-molecule BTK inhibitors for the treatment of autoimmune conditions. The design strategy of irreversible kinase inhibitors, as well as the extensive modeling and crystallographic support which allowed rapid progress of the program into the clinic, will be disclosed. The culmination of these strategies identified ABBV-105, a selective, covalent inhibitor that is efficacious in a preclinical model for RA.

2:40 NEW: Protein Binding Pockets Design Strategy to Enable Prospective Lead Discovery

Gerard Rosse, PhD, President, Arrival Discovery LLC

The presentation will focus on exploiting 3D protein surface information of multiple protein families such as GPCRs, Kinases, PDEs and PPIs to generate a prospective small molecule collection. This pocketome approach is combined with advanced automation technologies for chemistry, purification and compound management to expedite lead finding and maximize drug discovery. The value of an industrial approach to interrogate allosteric and orthosteric protein binding sites for intelligent design of small molecules and the changing landscape of automated chemistry and Super Critical Fluid chromatography within modern medicinal chemistry to reduce costs and increase prodcutivity, will be examplified with case studies of exploratory phase programs.

3:10 NEW: Targeting Inflammation with RIPK1 Inhibition

Allison Beal, PhD, Manager and Associate Fellow, Innate Immunity RU, GlaxoSmithKline

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Inhibition of Autoimmune Pathways with Dual Inhibition of JAK1 and TYK2: Discovery of PF-06700841

Andrew Fensome, PhD, Associate Research Fellow, Medicines Design, Pfizer

The Janus (JAK) kinases are a family of four non-receptor tyrosine kinases that modulate cytokine signaling through the Signal and Transduction of Transcription (STAT) pathways. The JAK kinases (JAK1, JAK2, JAK3 and TYK2) are important in a variety of cell types in the innate and adaptive immune system. I describe a series of selective JAK1/ TYK2 inhibitors for a range of inflammatory disorders such as inflammatory bowel disease, systemic lupus erythematosus and psoriasis. An important part of our program has been our understanding of PK:PD developed from our extensive experience with tofacitinib (Xeljanz ™) in the clinic and in preclinical animal models. The lead is a well behaved molecule with excellent in-vitro potency and a superior off-target poly-pharmacology profile. PF-06700841 is currently in Phase 2 clinical study.

5:00 NEW: Oral Integrin-Specific Peptide Antagonist for Ulcerative Colitis 

Larry Mattheakis, PhD, Vice President, Biology, Protagonist Therapeutics

5:30 Breakout Discussions - View All Breakouts

6:15 Close of Day

6:30 Dinner Short Courses*

*Premium or separate registration required.

Thursday, April 11

8:00 am Morning Coffee

8:45 Plenary Session Remarks from Event Director

Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute

8:50 Plenary Keynote Introduction

Timothy Craig, PhD, HarkerBio

8:55 Plenary Keynote: New Ways of Targeting K-Ras

Frank McCormick, PhD, Professor, HDF Comprehensive Cancer Center, University of California San Francisco

Efforts to find drugs that bind K‐Ras directly have increased recently, enabled by NMR‐based fragment screening, di-sulfide tethering, in silico drug design and biophysical methods such as Second Harmonic Generation (SHG). We will report progress on attacking two sites in the K‐Ras protein; cysteine‐185 (the site of prenylation), and histidine‐95, a residue unique to K‐Ras, to develop covalent K‐Ras inhibitors, as well as compounds identified by SHG and other methods.

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

NEW INFLAMMATION TARGETS FOR SMALL MOLECULES

10:40 Chairperson’s Remarks

Snahel Patel, PhD, Scientist, Discovery Chemistry, Genentech, Inc.

10:45 Pharmacological Regulation of the Keap1-NRF2 System Unveils Mitochondrial Targeting in Inflammation

Michelangelo Campanella, PhD, PharmD, Professor and Unit Head, Mitochondrial Cell Biology and Pharmacology, Research Group RVC and University College London Consortium for Mitochondrial Research

My talk will report upon Nrf2 inducers as pharmacological tolls in mitochondrial quality control operated by targeted autophagy. It will also dwell on their targeting of mitochondrial pathways which define autoimmunity and inflammation. The presentation will therefore elaborate on the prominent in cell activity of the non-covalent Keap1-Nrf2 protein-protein interaction (PPI) inhibitor PMI, structurally distinct from the covalent Keap1 modifiers (e.g., sulforaphane) and highlight promising ligands targeting mitochondrial pathways involved in the inflammatory response.

11:15 Novel Small Molecule E3 Ligase Activators as Anti-Inflammatory Agents

Kumar Suresh, PhD, Senior Director, R&D Biology, Progenra, Inc.

In this talk, I will present for the first time discovery and characterization of novel E3 ligase activators that suppress TH2 and TH17 differentiation and exhibit robust anti-inflammatory properties. Nedd4-family E3 ligases, including Itch, negatively regulate inflammatory immune responses by suppressing TH2 and TH17 differentiation and cytokine production. Genetic disruption of Itch leads to the development of multi-system immune disorders and lung inflammation.

11:45 CETSA® Enabled Drug Discovery

Michael Dabrowski, PhD, CEO, Pelago Bioscience

CETSA allows quantification of target engagement under relevant physiological conditions, which is prerequisite for achieving the intended efficacy. Over the last 8 years CETSA has been applied in hundreds of studies from early target validation to analysis of clinical samples. In his talk Michael will explore examples of applications and also discuss future perspectives in enabling drug discovery using the CETSA method.

12:00 pm Targeting TRAF6 E3 Ligase Activity with Small Molecules Combats Chronic Inflammation and Autoimmunity

Kamyar Hadian, PhD, Group Leader, Helmholtz Zentrum München

Constitutive NF-κB signaling represents a hallmark of chronic inflammation and autoimmune diseases. The E3 ligase TRAF6 acts as a key regulator bridging innate immunity, pro-inflammatory cytokines, and antigen receptors to the NF-κB pathway. Here, we present an inhibitor of TRAF6-Ubc13 interaction that reduces TRAF6 activity in vitro and in cells. Importantly, this inhibitor ameliorated inflammation and improved disease outcomes of autoimmune psoriasis and rheumatoid arthritis in preclinical mouse models.

12:30 Enjoy Lunch on Your Own

1:30 Dessert Break in the Exhibit Hall with Poster Awards Announced

Poster Awards Sponsored by Domainex

TARGETING THE INNATE IMMUNE SYSTEM

2:15 Chairperson’s Remarks

Daniel Dairaghi, PhD, Senior Research Advisor, Medicinal Chemistry, Eli Lilly & Co.

2:20 Bacterial Mediated Chemical Transformations of Autoimmune Drug Metabolism

Jason Michael Crawford, PhD, Associate Professor, Departments of Chemistry and Microbial Pathogenesis, Yale University

Photorhabdus asymbiotica causes soft tissue infections of the skin. This bacterium produces the immunomodulator tapinarof during its pathogenic phase. Tapinarof is in phase 3 clinical trials to treat the skin disorders psoriasis and atopic dermatitis. We demonstrate that bacteria can transform tapinarof into other novel potent products that activate the pathways associated with clinical efficacy and kill inflammatory bacteria of the skin.

2:50 Discovery of Novel and Potent Spirocyclic RORγt Inhibitors

Chip Lugar, Senior Research Scientist, Discovery Chemistry Research, Eli Lilly and Company

RORγt is a ligand dependent transcription factor that serves as the master regulator of Th17 and other IL-17 producing immune cells. It has become an important target for the treatment of autoimmunity, especially conditions that respond to anti-IL-17 antibodies such as psoriasis. A screening effort yielded substituted 4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-2'-carboxamides. We will present optimization of this novel spirocyclic scaffold from a weak screening hit to a potent RORγt inhibitor for use in vivo studies to define the level and duration of target engagement required for efficacy.

3:20 Targeting ROR and Other Nuclear Hormone Receptors: Chemistry Challenges and Beyond

Scott Thacher, PhD, CEO, Orphagen

This presentation will cover the chemistry challenges we’ve faced targeting nuclear hormone receptor for inflammation and cancer. A sub-theme will be “finding the right indication for druggable nuclear receptors.” I will also discuss our second-in-line program for antagonists to steroidogenic factor-1 (NR5A1).

3:50 Networking Refreshment Break

4:20 NEW: Breakout Discussion Report-Outs

Daniel Dairaghi, PhD, Senior Research Advisor, Medicinal Chemistry, Eli Lilly & Co.
Derek Cole, PhD, Senior Director, GI Medicinal Chemistry, Gastroenterology Drug Discovery Unit, Takeda Pharmaceuticals
Noel S. Wilson, MSc, Senior Scientist III, Discovery Chemistry and Technology, AbbVie

4:50 Targeting Soluble TNF to Eliminate Chronic Inflammation without Immunosuppression

RJ Tesi, MD, CEO/CMO, Inmune Bio

INB03 is a selective inhibitor of soluble TNF that is a potent anti-inflammatory agent that is not immunosuppressive. Current drug development leverages that important biology as part of therapy for cancer, neurodegenerative diseases and NASH. INB03 is significantly different from existing non-selective TNF inhibitors that block both soluble TNF (the BAD TNF) and trans-membrane TNF (the GOOD TNF). This difference makes all of the difference in safety, efficacy and therapeutic opportunity.

5:20 GSNOR Inhibitors for Inflammatory, Auto-Immune, and Oxidative Stress Based Diseases: RA, IBD, and NASH

Matthews O. Bradley, PhD, Chairman, President and Founder, SAJE Pharma, LLC

S-nitrosoglutathione Reductase (GSNOR) regulates nitrosylation signal transduction pathways and is over-expressed in many inflammatory human diseases. We identified, using X-ray crystallography and predictive in vitro assays, inhibitors of GSNOR that are potent, selective, orally bioavailable, and safe. The compounds inhibit oxidants, cytokines, chemokines, and inflammatory cells both in vitro and in vivo. The lead compound, SPL-891.1, is active in models of RA, IBD, and NASH among others.

5:50 Close of Conference