2013 Archived Content

Fourth Annual

Anti-Inflammatories

Small Molecule Approaches

April 16-17, 2013

CHI's Anti-Inflammatories: Small Molecule Approaches continues to be the ONLY meeting in the inflammation field that focuses on the discovery and development of oral or small-molecule based drug candidates. Anti-body based therapies, while effective and safe, are costly and harder to administer than an oral pill.  With the JAK inhibitors progressing in the clinic and one recently approved by the FDA, the promise of a new anti-inflammatory as good as the non-steroidal anti-inflammatories (NSAIDS) but without the gastric side effects, is tangible. Other oral anti-inflammatory drug candidates are on the horizon as well. This year's meeting will provide an update and highlight the medicinal chemistry optimizations that are allowing kinase inhibitor candidates to advance in clinical trials. Non-kinase targets will be a focus as well.

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TUESDAY, APRIL 16


Scientific Advisor: Martin Braddock, Ph.D., Senior Principal Scientist, Inflammation, Neuroscience and Respiratory Global Medicines Development, AstraZeneca

7:00 am Registration and Morning Coffee


BTK and JAK Inhibitors for Inflammation 

8:00 Chairperson’s Opening Remarks

Peter H. Schafer, Ph.D., Senior Principal Investigator, Translational Development, Celgene Corporation

 

Suvit Thaisrivongs » 8:10 FEATURED PRESENTATION

Targeted Covalent-Reversible Inhibitors for Bruton’s Tyrosine Kinase

Suvit Thaisrivongs, Ph.D., Executive Director, Chemistry, Pfizer

One strategy for optimizing pharmacological potency and selectivity for a number of challenging targets is to engage the non-catalytic cysteine residues with covalent inhibitors. Moreover, the utilization of a covalent inhibitor that reversibly forms an adduct is attractive as it may provide the pharmacodynamic benefit with reduced liability of long-lived irreversible protein adducts. Structure-based design led to the discovery of such a class of inhibitors for BTK. The optimized compound has been shown to be efficacious in several pre-clinical animal models of arthritis and autoimmune diseases. This offers promise as a therapeutic candidate for the treatment of autoimmune and inflammatory diseases.

8:50 Design and Characterization of Targeted Covalent Inhibitors of BTK

C. Eric Schwartz, Ph.D., Senior Director, Chemistry, Celgene Avilomics Research

One strategy for optimizing pharmacological potency and selectivity for a number of challenging targets is to engage the non-catalytic cysteine residues with covalent inhibitors. Moreover, the utilization of a covalent inhibitor that reversibly forms an adduct is attractive as it may provide the pharmacodynamic benefit with reduced liability of long-lived irreversible protein adducts. Structure-based design led to the discovery of such a class of inhibitors for BTK. The optimized compound has been shown to be efficacious in several pre-clinical animal models of arthritis and autoimmune diseases. This offers promise as a therapeutic candidate for the treatment of autoimmune and inflammatory diseases.

9:20 Potential of Selective BTK Inhibitors for Treating Autoimmune Diseases

Seng-Lai Tan, Ph.D., Consultant, Global Medical Affairs, F-Hoffmann-La Roche Ltd.

BTK may contribute to the development of autoimmune diseases by mediating the production and effector function of (auto)antibodies. Consistently, a selective and reversible BTK inhibitor produces efficacy in models of rheumatoid arthritis and systemic lupus erythematosus. The data provide a proof-of-concept for developing BTK inhibitors as therapeutics for these diseases.

9:50 Networking Coffee Break

10:15 Small Molecule BTK Inhibitors: An Update from Pharmacyclics

Longcheng Wang, Ph.D., Research Scientist III, Medicinal Chemistry, Pharmacyclics

This presentation will provide an overview of Pharmacyclics’ small molecule BTK inhibitor program, including second generation molecules for autoimmune indications and PCI-32765 which is in phase III clinical trials for lymphoma including CLL and MCL.

10:45 Discovery and Optimization of Selective JAK1 Inhibitors as Potential Treatments for Rheumatoid Arthritis

Mark Zak, Ph.D., Scientist, Discovery Chemistry, Genentech

JAK1 inhibitors exhibiting selectivity over JAK2 may hold the potential to maximize therapeutic efficacy against RA and other immune disorders, while minimizing unwanted anemia. Our strategies to identify selective and orally bioavailable JAK1 inhibitors will be presented, and the preclinical characterization of the lead molecule will be described.

11:15 Panel Discussion: Combatting Inflammation: What's Ahead?

Moderator: Seng-Lai Tan, Ph.D., Consultant, Global Medical Affairs, F-Hoffmann-La Roche Ltd.


Panelists:

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

Peter H. Schafer, Ph.D., Senior Principal Investigator, Translational Development, Celgene Corporation

Suvit Thaisrivongs, Ph.D., Executive Director, Chemistry, Pfizer

  • challenges and opportunities for kinase inhibitors as anti-inflammatories
  • other/newer targets for small molecules besides kinases
  • connections with other pathways/indications: regeneration, repair, remodeling?
  • mAB v. small molecules: is there a place for both?
  • what can we learn from biologics? future market considerations?
  • macrocyclics' future in inflammation field
  • ideas and progress in precision/personalized medicine in anti-inflammatories

 

DiscovRx11:45 Luncheon Presentation: BioMAP® Profiling: To B or Not To B

Alison O'Mahony, Ph.D., Director, Inflammation Biology, BioSeek, a division of DiscoveRx

Screening compounds in primary human cell BioMAP® systems designed to model diseased tissues reinstates a more physiological approach to drug discovery. Here, we present BioMAP® analysis of two BTK inhibitors revealing cell-selectivity, efficacy and safety related activities. Ibrutinib is broadly active on endothelial, epithelial, smooth muscle cells and fibroblast-based systems, while GDC-0834 is more selectively active in the BT system. Using these examples, we will show how BioMAP® can be used to guide pre-clinical development.

1:00 pm Session Break


Macrocyclics (Mostly) and Inflammation 

1:25 Chairperson’s Remarks

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

1:30 Discovery and Characterization of JAK1 Selective Macrocycles from a Cell-Based HTS Campaign

Jennifer Venable, Ph.D., Principal Scientist, Immunology Chemistry, Janssen Research & Development, LLC

2:00 Apremilast, a Targeted PDE4 Inhibitor in Development for Psoriatic Arthritis, Psoriasis, and Other Inflammatory Conditions

Peter H. Schafer, Ph.D., Senior Principal Investigator, Translational Development, Celgene Corporation

A premilast is an oral small molecule specific inhibitor of PDE4 with promising clinical efficacy in psoriasis and psoriatic arthritis. The expression of PDE4 in psoriatic skin and arthritic synovium, and the effects of apremilast on synovial fibroblasts, osteoclasts, osteoblasts, and osteocytes will be presented.

2:30 Nanocyclix: Potent and Selective Inhibitors for Novel Kinases in Cancer, CNS, Inflammation and Metabolic Diseases

Jan Hoflack, Ph.D., Head, Drug Discovery, ONCODESIGN Biotechnology

The Nanocyclix platform consists of low molecular weight macrocyclic kinase inhibitors that are exquisitely selective due to a high degree of shape complementarity with the ATP binding pocket. Multiple “First in Class” opportunities will be described in different therapeutic areas and will include detailed structural information on binding modes and selectivity generation.

3:00 Sponsored Presentation (Opportunity Available)

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

4:00 Macrocycles for Drug Discovery - Identification of Small Molecule Synthetic Macrocycle Antagonists of Human IL17A

Nick Terrett, Ph.D., CSO, Ensemble Therapeutics Corporation

Ensemble Therapeutics has developed a DNA-programmed chemistry platform for the rapid synthesis and screening of macrocycles (EnsemblinsTM). Using this platform, small molecule macrocyclic compounds have been discovered that are nanomolar inhibitors of the interaction of the IL17A cytokine with its receptor. These compounds are anti-inflammatory in IL17-dependent animal inflammatory models and optimized for oral bioavailability.


Jack Szostak» 4:30 PLENARY KEYNOTE

mRNA Display: From Basic Principles to Macrocycle Drug Discovery

Jack W. Szostak, Ph.D., Investigator, Howard Hughes Medical Institute; Professor of Genetics, Harvard Medical School; Nobel Laureate - Biography 

The covalent attachment of a nascent protein or peptide to its own mRNA allows the in vitro selection of functional proteins and peptides from large libraries. This approach has recently been extended to the in vitro selection of highly modified cyclic peptides, a promising class of therapeutic agents.

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

6:30 End of Day

7:00 - 10:00 Complimentary Shuttle Bus Roundtrips to Downtown San Diego, Courtesy of Hilton San Diego Resort & Spa



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