2016 Archived Content

Autoimmunity - Small Molecule Approaches Header

Small molecule-based therapies for the treatment of autoimmune diseases are much sought after because of the convenience oral-based therapies offer to patients, especially for chronic-type diseases. Now that more is known about the intracellular, biologics-inaccessible targets against which new small molecule, cell permeable agents can be developed, progress is rapid. Indeed, the past few years have witnessed the launch of a new class of oral therapies for RA (rheumatoid arthritis) that target intracellular kinases. Cambridge Healthtech Institute's "Autoimmunity - Small Molecule Approaches" one-day symposium will cover the progress of new small-molecule drug candidates and the promise of emerging intracellular drug targets in the autoimmune disease arena.

Final Agenda


• September 19 Symposium: Autoimmunity – Small Molecule Approaches

• September 20-21 Conference: Targeting Cardio-Metabolic Diseases

• September 21-22 Conference: Kinase Inhibitor Discovery

Monday, September 19

7:00 am Registration Open and Morning Coffee


8:30 Chairperson’s Opening Remarks

Kamal Puri, Ph.D., Director, Immunology & Inflammation, Celgene Corp.

8:40 FEATURED PRESENTATION: Modulators of RORγ for the Treatment of Autoimmune Diseases

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

RORγ is a nuclear hormone receptor expressed in Th17 cells and distinct subsets of lymphoid cells, including innate lymphoid cells (ILC), and γδ T-cells. RORγ 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.

9:40 Quinoline Tertiary Alcohols as RORgt Modulators for the Treatment of Psoriasis

Kristi Leonard, Ph.D., Associate Scientific Director, Immunology Research, Janssen Research & Development

The IL-23/IL-17 pathway plays an important role in the pathogenesis of psoriasis and biologics targeting IL-23 and IL-17 are clinically validated for the treatment of psoriasis. The inhibition of Th17 cell differentiation and IL-17 production through modulation of the RORgt receptor has generated much interest. Optimization of a high-throughput screening hit produced potent quinoline tertiary alcohol modulators of RORgt that are full inverse agonists.

10:10 Coffee Break


10:40 Discovery of the highly specific BTK inhibitor M2951 and Pharmacodynamic Modeling of BTK Occupancy versus Efficacy in RA and SLE models

Roland Grenningloh, Ph.D., Director, Preclinical Pharmacology, EMD Serono

Bruton’s tyrosine kinase (BTK) is a promising target for the treatment of autoimmune disease such as RA and SLE. We have developed M2951, a novel, highly selective BTK inhibitor that is suitable for the treatment of chronic diseases. M2951 potently inhibits BCR- and FcR-mediated signaling and displays robust efficacy in RA and SLE models. Pharmacodynamic modeling showed that mean BTK occupancy of 80 % led to near complete disease inhibition.

11:10 Design of a JAK3 Inhibitor to Interrogate JAK Signaling

Suvit Thaisrivongs, Ph.D., Head of Immunoscience Chemistry, Pfizer Worldwide R&D

JAK3 signals in pair with JAK1 to transduce signal elicited from six known cytokines (IL-2, IL-4, IL-7, IL-9, IL-15 & IL-21) binding to the gamma-common chain cytokine receptors. We have identified a JAK inhibitor which showed JAK3 selective inhibition in biochemical and cellular assays. JAK inhibitors, targeting multiple JAK isoforms, are currently utilized in clinical practice or being developed for the treatment of various inflammatory and oncological diseases.

11:40 Enjoy Lunch on Your Own


1:40 Chairperson’s Opening Remarks

Irina Kufareva, Ph.D., Project Scientist, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego

1:50 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, enters Phase I clinical trials this year. Our design toward selective immunoproteasome inhibitors will be discussed.

2:20 KPT-350, a Selective Inhibitor of Nuclear Export (SINE) Compound, Targets Multiple Autoimmune Processes in Lupus

Margaret S. Lee, Ph.D., Vice President, Research & Translational Development, Karyopharm Therapeutics, Inc.

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.

2:50 Mechanism of Action and Clinical Efficacy of mTOR Blockade in Lupus

Andras Perl, M.D., Ph.D., Professor of Microbiology and Immunology, Chief, Division of Rheumatology, State University of New York, UMU, College of Medicine

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting 1.5 million Americans with ~10% mortality over 5 years. Our recent studies unveiled a significant involvement of the mechanistic target of rapamycin (mTOR) in abnormal T-cell activation and lineage specification and autoantibody production in SLE. In accordance with a critical role for mTOR in pathogenesis, rapamycin reduced disease activity in a recently completed clinical trial.

3:20 Refreshment Break

4:00 Targeting Chemokine Receptors for Autoimmunity

Irina Kufareva, Ph.D., Project Scientist, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego

Chemokines are a family of 7-12 kDa secreted proteins that control cell migration in the context of development, immunity, inflammation, and cancer, all by virtue of their interaction with 7TM cell surface receptors. Inhibitors of receptor-chemokine interactions attract immense attention in several therapeutic areas. By a combination of molecular modeling, biophysical and functional experiments, and X-ray crystallography we elucidate the structural determinants of these interactions, with the goal of rationalizing the discovery of therapeutics targeting the chemokine receptor axis. 

4:30 Inhibition of an E2/E3 Ubiquitin Ligase Protein-Protein Interaction as a Novel Strategy to Counteract Autoimmune Diseases

Kamyar Hadian, Ph.D., Principal Investigator, Head of Assay Development and Screening Platform, HelmholtzZentrum München, Germany

This lecture will give insights into the discovery of a novel E2/E3 protein-protein interaction small molecule inhibitor that we were able to validate and characterize in a variety of biochemical as well as cell-based assays including primary mouse and human cells. More importantly, we can show that this first-in-class inhibitor is effective in pre-clinical autoimmune mouse models for Psoriasis as well as Rheumatoid Arthritis.

5:00 Targeting Inflammatory Bowel Diseases (IBD)

Kamal Puri, Ph.D., Director, Immunology & Inflammation, Celgene Corp.

5:30 Close of Symposium

* Separate registration required for Short Courses, Symposia, Training Seminar