Eighth Annual

Inflammation Inhibitors

Small Molecule Approaches for Oral-Based Therapeutics

April 24-25, 2017 | Sheraton San Diego Hotel & Marina

Interest in developing small molecule-based therapies for chronic inflammation remains strong despite the success of biologics for treating inflammation-related conditions such as rheumatoid arthritis. Small molecule agents, in contrast to biologics, can enter the cell and therefore act on intracellular targets which provides two advantages over biologics: 1) They can be developed into oral-based medications which are more convenient for the patient 2) There are a greater number of targets to aim at. Indeed a few oral-based kinase inhibitors for autoimmune indications were launched a few years ago and several more are in late stage development. This conference convenes medicinal chemists and discovery biologists to share their work and stay abreast of the rapid advances in developing new oral-based agents to combat different forms of chronic inflammation, which is at the nexus of several diseases.

Final Agenda

Monday, April 24

7:00 am Registration and Morning Coffee


8:00 Chairperson’s Opening Remarks

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

Dustin McMinn8:10 FEATURED PRESENTATION: Development of Immunoproteasome Subunit Selective Inhibitors

Dustin McMinn, Ph.D., Director, Head of Medicinal Chemistry, Kezar Life Sciences, Inc.

Selective immunoproteasome inhibition blocks inflammatory cytokine production and alters pro-inflammatory T-cell plasticity without affecting cell viability. Animal models of rheumatoid arthritis, type-I diabetes, multiple sclerosis, IBD, and lupus maintain normal immune function while responding well to small-molecule immunoproteasome inhibitors. Kezar’s first candidate from this compound class, KZR-616, entered Phase I clinical trials in summer of 2016. Our design toward KZR-616 and other selective immunoproteasome inhibitors will be discussed.

8:40 STING (Stimulator of Interferon Genes)-Dependent Pathways and New Drug Targets

Sasha_PoltorakSasha (Alexander) Poltorak, Ph.D., Associate Professor, Integrative Physiology and Pathobiology, Tufts University

We present evidence that activation of STING in T cells not only induces a type I IFN response atypical of these cells, but also activates cell stress and apoptotic pathways, triggering profound T cell death. These observations imply that STING-targeted therapeutics may potentially lead to T cell deficiencies, or, conversely could be beneficial for the elimination of pathological T cells in the case of autoimmune disease, T cell lymphomas, or organ transplantation.

Hitgen9:10Discovery of Small Molecule Ligands to STING

Barry Morgan, Ph.D., CSO, Hitgen Ltd.

HitGen will outline their approach to the design and interrogation of DNA encoded small molecule libraries, exemplified by the discovery of small molecule ligands to Stimulator of IFN Genes (STING). These non-nucleoside compounds represent promising starting points (low molecular weight and desirable physical properties) for medicinal chemistry optimization.

9:40 Coffee Break

10:05 Discovery of NF-kappa-B-Inducing Kinase (NIK) Inhibitors

Walter_KeungWalter Keung, Ph.D., Senior Scientist, Medicinal Chemistry, Takeda California

NF-kB-inducing kinase (NIK, MAP3K14) is a key component of the non-canonical NF-kB pathway, and a central node in pathways commonly activated in autoimmune and inflammatory disorders. Here, we describe a fragment and structure based approach to the optimization of novel and selective series of NIK inhibitors, which capitalized on an unexpected flipped binding mode. Broader pharmacological profiling of these molecules will also be described.

10:35 Biomarker Discovery and Development of PTG-200, an Oral Peptide Antagonist of IL-23 Receptor

Larry_MattheakisLarry Mattheakis, Ph.D., Vice President, Biology, Protagonist Therapeutics

Clinical studies show that blocking IL-23 function has therapeutic applications in inflammatory bowel disease. We have developed PTG-200, a potent peptide that binds and blocks downstream signaling of the IL-23 receptor, expressed on gut innate lymphoid cells. PTG-200 is orally stable and in rat colitis models results in significant improvements in disease, including histopathology. We also identified biomarkers that are PTG-200 dose dependent and correlate with efficacy; their potential clinical applications will be discussed.

11:05 KPT-350, a Selective Inhibitor of Nuclear Export (SINE) Compound, Targets Multiple Autoimmune Processes in Lupus

Christian Argueta, PhD, Scientific Program Manager, Biology, Karyo Pharma

Exportin-1 (XPO1) is the sole nuclear exporter of multiple anti-inflammatory regulatory proteins and transcription factors relevant to systemic lupus erythematosus (SLE) disease pathology. KPT-350 is an orally bioavailable, reversible, small-molecule inhibitor of XPO1 with potent effects on murine lupus in vivo. KPT-350 treatment reduces germinal center reactions, auto reactive plasma cells, pro-inflammatory cytokines and autoantibodies leading to improvements in nephritis and proteinuria in lupus prone mice. Thus inhibition of XPO1 represents a novel therapeutic approach for SLE.

11:35 Lunch on Your Own



1:15 Chairperson’s Remarks

John Robinson, Ph.D., Director, Medicinal Chemistry, Array Biopharma

Steven Goldberg1:20 FEATURED PRESENTATION: Discovery of a Series of Thiazole RORγt Inverse Agonists

Steven Goldberg, Ph.D., Associate Scientific Director, Immunology, Janssen R&D

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 γt (RORγt). Blocking the production of pro-inflammatory cytokines by RORγt modulation has the potential to be an effective treatment for autoimmune diseases. A promising series of thiazole RORγt inverse agonists has been identified and our optimization efforts will be discussed.

1:50 Small Molecule Modulators of RORγ

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 fragment screening, structure-based design and optimization, which led to the discovery of potent, selective ROR g modulators with favorable ADME properties suitable for in-depth profiling and characterization.

2:20 From Multiple Hit Series to the Clinical Candidate for RORγt Using DNA Encoded Library Technology

Sanne_GladSanne Glad, Ph.D., Principal Scientist, Project Leader, Lead Discovery Nuevolution

The nuclear hormone receptor RORγt is a master regulator of IL-17A production, which triggers inflammatory disease. We have identified nanomolar potent small molecule inverse agonists from screening 830 million DNA-encoded compounds against the RORγt-ligand binding domain. Hit-to-lead optimization led to a preclinical candidate with attractive DMPK properties, high oral bioavailability, strong in vivo efficacy across several anti-inflammatory animal models, and a benign safety profile.

2:50 Late Breaking Presentation: Structural Basis of Orthosteric and Allosteric Inhibition of Chemokine Receptors

Yi Zheng, Ph.D., Postdoctoral Fellow, Tracy Handel Laboratory, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego

3:20 Selected Poster Presentations

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


PROTACs: Inducing Protein Degradation as a Therapeutic Strategy

Craig M. Crews, Ph.D., Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology; Professor, Chemistry & Pharmacology, Yale University

Enzyme inhibition has proven to be a successful paradigm for pharmaceutical development, however, it has several limitations. As an alternative, for the past 16 years, my lab has focused on developing Proteolysis Targeting Chimera (PROTAC), a new ‘controlled proteolysis’ technology that overcomes the limitations of the current inhibitor pharmacological paradigm. Based on an “event-driven” paradigm, PROTACs offer a novel, catalytic mechanism to irreversibly inhibit protein function, namely, the intracellular destruction of target proteins.

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

6:30 Close of Day

Tuesday, April 25

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.

Topic: Developing Kinase Inhibitors for Chronic Indications

Moderator: John Robinson, Ph.D., Director, Medicinal Chemistry, Array Biopharma

  • 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 to Better 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
  • Phenotypic screening
  • Irreversible versus reversible inhibitors. Will irreversible inhibitors drive a boost in approvals?

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

Dustin McMinn, Ph.D., Director, Head of Medicinal Chemistry, Kezar Life Sciences, Inc.

8:35 A Twisted Road to the Discovery of BMS-986142: Using Locked Atropisomers to Drive Potency in a Reversible Inhibitor of Bruton’s Tyrosine Kinase (BTK)

Joseph_TinoJoseph Tino, Ph.D., Senior Principal Scientist, Immunoscience Discovery Chemistry, BristolMyers Squibb

Bruton’s tyrosine kinase (BTK) plays a central role in multiple cell types linked to autoimmune diseases. BTK inhibitors are anticipated to be important clinical options for fighting rheumatoid arthritis and lupus. This presentation details the structure-activity relationships leading to a novel series of carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Improvements in potency and selectivity by locking the two atropisomeric centers will be featured. With an excellent efficacy and tolerability profile, BMS-986142 has advanced into clinical studies.

9:05 A First-in-Class Allosteric Inhibitor of TYK2 as a Potential Treatment for Inflammatory Autoimmune Diseases

Stephen_WrobleskiStephen Wrobleski, Principal Investigator, Immunoscience Chemistry, Bristol-Myers Squibb

Tyrosine kinase 2 (TYK2) is a member of the JAK family of kinases and is involved in signaling through the receptors for several pro-inflammatory interferons and interleukins. BMS-986165 is a highly potent and exquisitely selective TYK2 inhibitor that binds to the unique pseudokinase domain of TYK2 and functions through an allosteric mechanism. I will describe the medicinal chemistry efforts and structure-based optimization strategies that led to the identification of BMS-986165 as a promising clinical candidate with first-in-class potential.

TCG Life Sceinces9:35 Coffee Break in the Exhibit Hall with Poster Viewing


10:30 ARRY-624: A TYK2-leaning, JAK Inhibitor: A First-in-Class Small Molecule Selectively Targeting the IL-12/23 Pathways

John Robinson, Ph.D., Director, Medicinal Chemistry, Array Biopharma

Pan JAK inhibitors block signaling of >20 cytokines & growth factors, effect both NK and CD8+ T-cell populations, and exhibit increased risk of infection & malignancy clinically. We hypothesized that a Tyk2-targeted kinase inhibitor, such as ARRY-624, which does not engage JAK1/3, may lead to differentiated efficacy and clinical safety vs. currently available treatment options. This profile allows for selective modulation of IL-12 (Th1) and IL-23 (Th17) pathways, while sparing IL-2/IL-7 and IL-15 (g-chain-utilizing cytokines).

11:00 Inhibition of Autoimmune Pathways with Dual Inhibition of JAK1 and TYK2

Brian_GerstenbergerBrian Gerstenberger, Ph.D., Principal Scientist, Medicinal Chemistry, Pfizer

The JAK kinases (JAK1, JAK2, JAK3 and TYK2) are important in both the innate and adaptive immune system. The current work describes the discovery of a series of selective JAK1/ TYK2 inhibitors. We identified a series of ATP competitive pyrimidines from an early library lead, and through a structurally enabled program drove the biological profile and property space to advance the lead compound (PF-06700841) currently in clinical studies.

11:30 Discovery and Profiling of Novel, Intestinally-Restricted Oral Pan-JAK Inhibitors for the Treatment of Inflammatory Bowel Diseases

Jennifer Kozak, Ph.D., Research Scientist, Medicinal Chemistry, Theravance Biopharma

There remains a significant need for improved therapies to treat inflammatory bowel diseases, including ulcerative colitis (UC). The oral JAK inhibitor tofacitinib has demonstrated clinical effectiveness in treating UC patients in Phase 3 trials, although its usage may be limited by adverse events resulting from systemic drug levels. Here we report the structure-based design and profiling of a series of novel, pan-JAK inhibitors designed to be intestinally-restricted thereby minimizing systemic side effects.

12:00 pm Close of Conference