Biologics have been useful in treating diseases of chronic inflammation such as multiple sclerosis or rheumatoid arthritis, but there is still an unmet medical need for more convenient and safer treatment options for such diseases. A few kinase inhibitors that fit these criteria have been recently launched and a few are in late-stage development. Join fellow drug discovery scientists at Cambridge Healthtech Institute’s fifth annual Anti-Inflammatories: Small Molecule Approaches day- and-a-half meeting track to stay abreast of the latest progress in the field of oral-based (mostly small molecules) inhibitors for inflammation. A focus will be on the chemical optimizations that have enabled the leading inflammation drug candidates to progress. Presentations on newer and non-kinase targets for combating inflammation will also be a part of the agenda.
Speakers were great and presented valuable data. Comprehensive conference and
Tina T., Associate Scientist, Biogen Idec
overview of most current inflammation targets and therapies.
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7:00 am Registration and Morning Coffee
8:00 Chairperson’s Opening Remarks
Seng-Lai “Thomas” Tan, Ph.D., Head, Cellular and Translational Immunology, EMD Serono Research and Development Institute, Inc.
8:10 Featured Presentation: B Cell Receptor Signaling Inhibitors for Treatment of Inflammatory Diseases
Kamal Puri, Ph.D., Associate Director, Research, Gilead Sciences, Inc.
B-cell receptor (BCR) signaling plays a critical role in activation and function of self-reactive B cells that contribute to autoimmune diseases. Recent data have established an important role for PI3Kdelta in coupling BCR to B-cell activation and inhibition of this pathway may represent a promising new strategy. This talk will focus on recent achievements in the mechanism of action, pharmacological properties, and preclinical activity of PI3Kdelta inhibitors, with a focus on their emerging role in treating autoimmune disorders.
8:40 Discovery and Optimization of BTK Inhibitors
Wendy Young, Ph.D., Director, Discovery Chemistry, Genentech
Bruton’s tyrosine kinase (BTK) plays a critical role in the development, differentiation and proliferation of B-lineage cells, making it an attractive target for the treatment of immunological disorders (e.g. RA, Lupus, MS, Asthma) as well as B-cell lymphomas. Ibrutinib, the most advanced BTKi in oncology indications, has proven highly effective, although there have been increasing reports of patients relapsing due to mutations, including such at Cys481. Our efforts leading to the design and development of our first clinical candidate, GDC-0834, will be described as well as our subsequent efforts that yielded second and third generation inhibitors. Crucially, such analogs remain highly active against Cys481 (and other) Btk mutants. SAR, crystal structures, DMPK, and efficacy data from examples of these series will be described.
9:10 A Novel Class of Selective SYK Inhibitors for Inflammation
Lars Burgdorf, Ph.D., Principal Scientist, Medicinal Chemistry, Merck KGaA, Germany
Spleen Tyrosine Kinase (SYK) is a promising target for the treatment of autoantibody-mediated diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We designed a new class of highly potent and selective SYK Inhibitors. We will present our drug discovery strategy for library design and compound optimization, including SAR, X-ray structures and selectivity profiles.
9:40 Coffee Break
10:05 Selective JAK1 Inhibition as a Therapeutic Strategy in Inflammation
Christel Menet, Ph.D., Senior Lead, Project Director, Autoimmune Disease, Galapagos
The lead compound, GLPG0634, is the first JAK1 selective compound that has demonstrated clinical efficacy and a favorable safety profile in two Phase IIA clinical studies in patients with rheumatoid arthritis. Discovery and SAR of the series will be presented.
10:35 Drug Discovery Strategy for the Identification of Potent and Selective RIP2 Kinase Inhibitors
Linda Casillas, Ph.D., Senior Scientific Investigator, Immuno-Inflammation Medicinal Chemistry, GlaxoSmithKline
RIP2 kinase plays a key signaling role downstream of the pattern recognition receptors (PRRs) NOD1 and NOD2. These PRRs have been linked to various auto-inflammatory conditions including an ultra-rare disease known as Blau Syndrome. Combining a broad screening strategy with rigorous lead optimization of multiple chemotypes in parallel, we have identified several potent and selective RIP2 inhibitors. This presentation will highlight some of the significant challenges and creative solutions that arose during this discovery program.
11:05 Sponsored Presentation (Opportunity Available)
11:35 Luncheon Presentation
Speaker to be Announced
12:05 pm Session Break
1:15 Chairperson’s Remarks
Christopher R Smith, Ph.D., Director, Chemistry, Takeda California
1:20 Epigenetic BET Inhibitors and Inflammation
Gerald Denis, Ph.D., Associate Professor, Cancer Center, Boston University School of Medicine
The BET family of related proteins, comprised of BRD2, BRD3, BRD4 and BRDT, has recently been shown to co-activate NFkappaB-regulated cytokine genes, and to play opposite roles in cancer and HIV latency. Small molecule BET inhibitors ablate cytokine transcription, but are not selective for any co-expressed isoform. Lack of selectivity is a benefit in some cases and a hazard in others. Experiments to probe mechanism should now advance this field.
1:50 Targeting Argenine Deaminases (PADs) and Methyl Transferases for Inflammation
Paul R. Thompson, Ph.D., Associate Professor, Department of Chemistry, TSRI, Scripps Florida
The Protein Arginine Deiminases (PADs) are important regulators of extracellular trap formation and gene transcription, whose activity is upregulated in multiple inflammatory diseases, including rheumatoid arthritis, lupus, and cancer. Herein, I discuss PAD inhibitor development and our success in validating the PADs as therapeutic targets for multiple inflammatory diseases. Additionally, I describe our efforts to develop citrulline-specific probes that are used to visualize and isolate citrullinated biomarkers of disease.
2:20 Sponsored Presentation (Opportunity Available)
2:35 Refreshment Break in the Exhibit Hall with Poster Viewing
3:20 Novel Small Molecular Ligands of KEAP1 Induce Protective NRF2-Dependent Anti-Inflammatory Responses in Neurodegenerative Models
Aleksey Kazantsev, Ph.D., Associate Professor, Neurology, Harvard Medical School and Massachusetts General Hospital
The study identified novel compounds, which induce canonical NRF2-dependent responses and are protective in Parkinson’s and Huntington’s disease models. In accord with the known anti-inflammatory effects of NRF2 activation, compounds potently repress an expression of inflammatory markers in activated microglial cells, macrocytes and in mouse brain. Reversible compound binding to the NRF2 inhibitor, KEAP1, was identified by a docking model and binding confirmed by mechanistic studies, suggesting a novel approach to activating the NRF2 pathway.
3:50 Disrupting NRF2 and Keap1 Protein Interaction with Non-Covalent Inhibitors
Laura Silvian, Ph.D., Principal Scientist, Physical Biochemistry, Biogen Idec
Keap1 binds to the Nrf2 transcription factor to enable its ubiquitination; blocking this interaction would upregulate genes that protect against oxidative stress. Cell-active compounds that modify cysteines in Keap1 effect the Nrf2-dependent pathway. We have identified and characterized non-covalent compounds that bind to the Keap1 Kelch-DC domain and block Nrf2 binding. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side effects due to non-specific cysteine modification.
4:20 Session Break
4:30 Plenary Keynote Presentation: Drug Discovery for Challenging Targets
James Wells, Ph.D., Professor, Pharmaceutical Chemistry and Cellular & Molecular Pharmacology, University of California San Francisco
I will present work from our lab for two classes of challenging targets: protein-protein interfaces and novel allosteric sites, both to activate and inhibit protein function. We use a site-directed fragment-based discovery method, called Tethering, coupled to HTS approaches that are well-suited to probing these challenging surfaces. These approaches have led to the discovery of potent and selective compounds and some with surprising properties that will be discussed.
5:30 Welcome Reception in the Exhibit Hall with Poster Viewing
6:30 Close of Day
7:30 am CONTINENTAL BREAKFAST and 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: Linda Casillas, Ph.D., Senior Scientific Investigator, Immuno-Inflammation Medicinal Chemistry, GlaxoSmithKline
• 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 better to discover safe and effective anti-inflammatory therapeutics?
Moderator: Christopher R Smith, Ph.D. Director, ChemistryTakeda California
• Next generation kinase inhibitors – opportunities and challenges
• Irreversible versus reversible inhibitors. Will irreversible inhibitors drive a boost in approvals?
• COPD; inhaled versus oral therapies – opportunities and challenges
Topic: Anti-inflammatories: Promises and Expectations
Moderator: Seng-Lai “Thomas” Tan, Ph.D., Head, Cellular and Translational Immunology, EMD Serono Research and Development Institute, Inc.
• Targeted delivery challenges
• Phenotypic screening approaches
• Small molecules v. antibody therapeutics
8:40 Chairperson’s Remarks (Sponsorship Opportunity Available)
8:45 Chemokine Receptors and Inflammation
Dan Dairaghi, Ph.D., Senior Director, Molecular Pharmacology and Biomarkers, ChemoCentyrx
The chemokine system, including chemokines and chemo-attractants, directs inflammatory responses, serving to precisely coordinate immune system cell movement. As drivers of the inflammatory response, chemokines and their receptors present opportunities for the development of new therapies. Each of ChemoCentryx’s novel small molecule drug candidates is designed to target a specific chemokine receptor, thereby blocking the inflammatory response driven by that particular chemokine while leaving the rest of the immune system unaffected.
9:15 Targeting the Immunoproteasome
Dustin McMinn, Ph.D., Associate Director, Medicinal Chemistry, Onyx Pharmaceuticals
Selective inhibition of the immunoproteasome (iP) inhibits cytokine production and alters T cell plasticity yet with no effect on cell survival. ONX-0914, a selective inhibitor of the β5i subunit of iP, is efficacious in autoimmune disease models. Computational modeling reveals a related analogue, PR-924, adopts a distinct binding mode that enhances β5i selectivity. Data potentiating our design of lead structures with excellent selectivity for the immunoproteasome will be presented.
9:45 Coffee Break in the Exhibit Hall with Poster Viewing
10:30 Oral Peptide Therapies for Inflammation
David Y. Liu, Ph.D., CSO, Protagonist Therapeutics, Inc.
11:00 Discovery and Synthesis of FLAP Inhibitors for the Treatment of Inflammatory Diseases
Alec Lebsack, Ph.D., Associate Scientific Director, Immunology Chemistry, Janssen Research & Development
Leukotrienes play a critical role in both acute and chronic inflammation, and 5-lipoxygenase-activating protein (FLAP) is a key protein involved in leukotriene biosynthesis. Previous programs targeting the nuclear membrane protein FLAP have been hampered by the lack of potency, developability challenges, and the potential for drug-drug interactions (DDI). This presentation will describe several approaches to small molecule lead generation for the Janssen FLAP inhibitor program. The positive differentiation from known FLAP inhibitors and structure-activity relationships for select series obtained from these approaches will be presented.
11:30 Novel Selective Inhibitors of Nuclear Export (SINE) are Highly Effective in Models of Autoimmune Diseases
Robert Carlson, Ph.D., Vice President, Preclinical Development and Product Leadership, Karyopharm Therapeutics
Exportin 1 (XPO1) is a protein that controls nuclear export of over 200 cargo proteins. Selective Inhibitors of Nuclear Export (SINE) are XPO1 inhibitors that kill cancer cells through nuclear retention and activation of tumor suppressor proteins. SINEs also force nuclear retention of proteins that play key roles in inflammation. In this talk, the efficacy of SINEs in models for a variety of autoimmune diseases will be reviewed.
12:00 pm Close of Track
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