Anti-Inflammatories: Small Molecule Approaches

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7:00 am Registration and Morning Coffee


Kinases, Jaks and Inflammation

8:00 Chairperson’s Opening Remarks

Jordan Fridman, Ph.D., Director, Pharmacology, Incyte

»8:10 Keynote Presentation:

Overview of Inflammation Signal Transduction Pathways and Connections to Cancer

Raffaella Sordella Raffaella Sordella, Ph.D., Assistant Professor, Cold Spring Harbor Laboratories
An association between the development of cancer and inflammation has long-been appreciated. Long-standing inflammation predisposes to cancer and aspects of tissue damage responses often correlate negatively with cancer stage and prognosis. In addition recent studies also indicated that inflammation could hamper tumors responses to drug treatment.

8:50 Discovery of Potent and Selective Jak1 / Jak2 Inhibitors for the Treatment of Cancer and Inflammation

James D. Rodgers, Ph.D., Executive Director, Medicinal Chemistry, Incyte Corp.

Inhibition of aberrant JAK-STAT signaling offers a new approach for the treatment
of cancer and inflammation. This presentation will describe the discovery of the dual
JAK1 / JAK2 selective inhibitor INCB018424 currently in clinical trials for the treatment
myeloproliferative neoplasms (MPNs) and psoriasis.

9:20 A Potent Jak3 Inhibitor with High Selectivity within the Janus Kinase Family - The Roles of Jak3 and Jak1 in Signal Transduction

Gebhard Thoma, Senior Investigator, Novartis Institutes for BioMedical Research, Basel

Genetic deficiency of Jak3 leads to abrogation of signal transduction through the common gamma chain and thus to immunodeficiency suggesting that specific inhibition of Jak3 kinase may result in immunosuppression. However, Jak1 always cooperates with Jak3 in signalling through gamma chain-containing receptors. We will provide evidence that Jak1 plays a dominant role over Jak3. These data challenge the notion that selective ATP-competitive Jak3 kinase inhibitors will be effective.

9:50 Networking Coffee Break in the Exhibit Hall with Poster Viewing


Syk Inhbitors for Inflammation

10:15 Application of Functional Screening Using Cultured Human Mast Cells for the Discovery and Optimization of Syk Kinase Inhibitors Leading to Fostamatinib

Rajinder Singh, Ph.D., Head, Medicinal Chemistry, Rigel

Use of cultured human mast cells in high throughput screening for identification of hits inhibiting immunoglobulin E (IgE) mediated activation of Fc receptor signaling leading to downstream inhibition of degranulation. Application of this paradigm to structure activity relationship (SAR) to one particular scaffold generated potent analogues and the discovery of orally bioavailable R406. Importantly R406 also blocks SYK-dependent Fc receptor mediated activation of monocytes, macrophages and neutrophils and B-cell receptor (BCR)-mediated activation of B lymphocytes. Formulation properties of R406 were further enhanced via synthesis of R788, fostamatinib, which has advanced to Phase 3 studies.

10:45 Science Supporting Development of the Syk Inhibitor Fostamatinib for Rheumatoid Arthritis

Martin Braddock, Ph.D., Senior Principal Scientist, Respiratory and Inflammation R&D, Astra Zeneca

In this presentation I will describe the scientific rationale supporting inhibition of the syk mechanism and its potential utility in the treatment of autoimmune disease. Focusing on the pre-clinical development of fostamatinib, I will present an overview of in vitro and in vivo data and discuss the potential of this drug in targeting disease mechanisms in patients with rheumatoid arthritis.

11:15 Selected Poster Presentation

11:30 Discovery and Development of a Highly Specific and Orally Bioavailable Syk Inhibitor PRT062607

Anjali Pandey, Ph.D., Vice President, Chemistry, Portola Pharmaceuticals, Inc.

PRT062607 is a novel and structurally distinct class of Syk inhibitor. PRT062607 is a potent inhibitor of the BCR-induced Syk signaling and cellular activation and FCeR-induced induced basophil degranulation in human whole blood. PRT062607 achieved statistically significant and dose dependent efficacy in animal models of rheumatoid arthritis. PRT062607 is currently evaluated in Phase 1 clinical trials.

12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own


Targeting GPCRs for Inflammation

1:25 Chairperson’s Remarks

William Pitts, Ph.D., Group Leader, Medicinal Chemistry, Bristol Myers Squibb

1:30 Pharmacological Profile of Selective S1P1 Agonists

Luca Piali, Ph.D., Director, Immunology, Actelion Pharma

We have characterized novel S1P1 receptor agonists both biochemically and pharmacologically. The compounds allow for quickly responsive lymphocyte count modulation and show efficacy in different animal models of autoimmune disease.

2:00 Discovery of Potent and Selective Sphingosine-1-Phosphate [S1P1R] Agonists

Robert M. Jones, Ph.D., Senior Director, Medicinal Chemistry, Arena Pharmaceuticals

The potent S1P1 agonist fingolimod has been shown to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability in MS and has recently been approved in the US, EU and Switzerland. Herein, we will highlight the design and synthesis of a new second generation series of S1P1 agonists, which are both potent and selective and have desirable safety and ADME profiles. We also disclose lead optimization efforts and efficacy of lead molecules in lymphocyte lowering in mouse after oral dosing and activity in several rodent models of autoimmunity.


2:30 Panel Discussion: Drug Development Challenges of Oral Anti-Inflammatories

Moderator: Jordan Fridman, Ph.D., Director, Pharmacology, Incyte



Betty Y. Chang, Ph.D., Director of Immunology, Pharmacyclics Inc.

Luca Piali, Ph.D., Director, Immunology, Actelion Pharma

William Pitts, Ph.D., Group Leader, Medicinal Chemistry, BMS

Rajinder Singh, Ph.D., Head, Medicinal Chemistry, Rigel

Rafaella Sordella, Ph.D., Assistant Professor, Cold Spring Harbor Laboratories

  • Why are kinase inhibitors meeting with such success in the clinic to date? What are potential upcoming pitfalls and how to avoid them?
  • What are some promising looking newer targets?
  • How will the cancer/inflammation connection be useful to drug development?
  • Optimal points of B cell intervention
  • Targeting MS/inflammation

3:15 Networking Refreshment Break in the Exhibit Hall with Poster Viewing


Non-Kinase Oral Drug Candidates Targeting Inflammation

4:00 Apremilast, an Orally Available PDE4 Inhibitor in Phase 3 Clinical Trials for the Treatment of Psoriasis and Psoriatic Arthritis

Peter Schafer, Ph.D., Director, Translational Development, Celgene Corporation

Apremilast is a novel, orally available small molecule that specifically inhibits phosphodiesterase 4 (PDE4) and thus modulates multiple pro- and anti-inflammatory mediators. It is active in animal models of both psoriasis and arthritis, reducing inflammatory processes in both the skin and the joint. Apremilast is currently under clinical development for the treatment of psoriasis, psoriatic arthritis, rheumatoid arthritis and other inflammatory and autoimmune diseases.

4:30 Targeting IL-17 with Novel Small Molecules: Next Generation Autoimmune Therapeutics

Daniel Vitt, Ph.D., CSO, R&D, 4SC AG

IL-17 is one of the key cytokines identified in the last years which is directly corelated with diseases like multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis. Driven by the discovery that Vidofludimus (4SC-101) is an orally available dual inhibitor of IL-17 and DHODH we have developed a completely new series of molecules with subnanomolar activity on IL-17 and INF-gamma secretion. New cellular and in vivo data will be presented.

5:00 Macrolides as a New Class of Orally Active Anti-Inflammatory Agents

Prabhavathi Fernandes, Ph.D., CEO, Cempra Pharmaceuticals, Inc.

Macrolide antibiotics have been known for decades to produce effects unrelated to its antibacterial use and have been used to treat late stage COPD patients to increase their steroid sensitivity. Cempra has identified leads from its macrolide library that show improved anti-inflammatory effects and have little or no antibacterial activity. Solithromycin, a new fluoroketolide in Phase 2 clinical development for bacterial pneumonia also shows more potent anti-inflammatory properties than any other macrolide. The mechanism of the inhibitory activity and results to date will be described.

5:30 Networking Cocktail Reception in the Exhibit Hall

6:30 End of Day

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