Cambridge Healthtech Institute 第10回

Inflammation Inhibitors
( 炎症抑制剤 )

自己免疫疾患と炎症に関連する経口治療薬の医薬品化学

2019年4月10日~11日

 

製薬業界では、炎症や自己免疫に関わる症状に対応する低分子ベースの薬剤を発見し、開発するための取り組みが活発化しています。関節リウマチに対応する初めての経口治療薬は、低分子のJAKキナーゼ阻害剤であり、数年前に発売されました。これらの抗炎症薬 (大半は低分子医薬品ですが、一部の大環状ペプチドや拘束性ペプチドも細胞内に浸透することができます) は、経口ベースであるため患者に大きな利便性をもたらすという点のみならず、炎症や自己免疫に関わる症状に影響する多くの細胞内分子についての科学的な知識を短時間で蓄積することができるという点でも注目を集めています。炎症抑制剤をテーマにしたこのカンファレンスプログラムでは、免疫学に関連する創薬標的を研究している化学や生物学の研究者が一堂に会し、この分野における新たな発見や医薬品化学研究の最新の成果について意見を交換します。


Final Agenda

Wednesday, April 10

12:30 pm Registration Open

12:45 Dessert Break in the Exhibit Hall with Poster Viewing

炎症と自己免疫疾患に対応する細胞内キナーゼ阻害剤 (および各種阻害剤)

1:30 Welcome Remarks

Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute

1:35 Chairperson’s Opening Remarks

Derek Cole, PhD, Director, Medicinal Chemistry, Takeda San Diego

1:40 FEATURED PRESENTATION: Discovery of a Cross-Species Potent and Selective Inhibitor of Receptor-Interacting Protein Kinase (RIPK1) Providing Protection in a Number of Immunological Models

Snahel Patel, PhD, Scientist, Discovery Chemistry, Genentech, Inc.

Regulation of cell death signaling is critical for the maintenance of homeostasis and prevention of disease. Necroptosis, a caspase-independent regulated form of cellular death, is emerging as an important mediator of a number of human pathologies. Activation of necroptotic signaling through TNF signaling or organ injury activates RIPK1 and RIPK3 leading to inflammatory cell death. We present the development of a cross-species potent and selective small molecule inhibitor of RIPK1 to explore the prevention of cell death in a number of disease models of inflammation.

2:10 Considerations in the Generation of Covalent BTK Inhibitors

Noel S. Wilson, MSc, Senior Scientist III, Discovery Chemistry and Technology, AbbVie

Bruton tyrosine kinase (BTK) plays a central role in signaling from the B-cell receptor, which has prompted the development of small-molecule BTK inhibitors for the treatment of autoimmune conditions. The design strategy of irreversible kinase inhibitors, as well as the extensive modeling and crystallographic support which allowed rapid progress of the program into the clinic, will be disclosed. The culmination of these strategies identified ABBV-105, a selective, covalent inhibitor that is efficacious in a preclinical model for RA.

2:40 Discovery of GS-9876: A Selective SYK Inhibitor for the Treatment of Autoimmune Inflammatory Disorder

Peter Blomgren, PhD, Research Scientist II, Medicinal Chemistry, Gilead Sciences, Inc.

3:10 Sponsored Presentation (Opportunity Available)

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 TYK2 Inhibitors

Andrew Fensome, PhD, Associate Research Fellow, Medicines Design, Pfizer

5:00 PTG-100: An Oral Integrin-Specific Peptide Antagonist for Ulcerative Colitis

David Y. Liu, PhD, CSO, Protagonist Therapeutics

5:30 Breakout Discussions

6:15 Close of Day

6:30 Dinner Short Courses*

*Premium or separate registration required.

Thursday, April 11

8:00 am Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee


8:45 Welcome Remarks from Lead Conference Director

Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute

8:50 Plenary Keynote Introduction

8:55 Plenary Keynote: New Ways of Targeting K-Ras

Frank McCormick, PhD, Professor, HDF Comprehensive Cancer Center, University of California San Francisco

Efforts to find drugs that bind K-Ras directly have increased recently, enabled by NMR-based fragment screening, di-sulfide tethering, in silico drug design and biophysical methods such as Second Harmonic Generation (SHG). We will report progress on attacking two sites in the K-Ras protein; cysteine-185 (the site of prenylation), and histidine-95, a residue unique to K-Ras, to develop covalent K-Ras inhibitors, as well as compounds identified by SHG and other methods.

9:45 Coffee Break in the Exhibit Hall with Poster Viewing

低分子医薬品による炎症治療の新たな標的

10:40 Chairperson’s Remarks

Snahel Patel, PhD, Scientist, Discovery Chemistry, Genentech, Inc.

10:45 Pharmacological Regulation of the Keap1-NRF2 System Unveils Mitochondrial Targeting in Inflammation

Michelangelo Campanella, PhD, PharmD, Professor and Unit Head, Mitochondrial Cell Biology and Pharmacology, Research Group RVC and University College London Consortium for Mitochondrial Research

My talk will report upon Nrf2 inducers as pharmacological tolls in mitochondrial quality control operated by targeted autophagy. It will also dwell on their targeting of mitochondrial pathways which define autoimmunity and inflammation. The presentation will therefore elaborate on the prominent in cell activity of the non-covalent Keap1-Nrf2 protein-protein interaction (PPI) inhibitor PMI, structurally distinct from the covalent Keap1 modifiers (e.g., sulforaphane) and highlight promising ligands targeting mitochondrial pathways involved in the inflammatory response.

11:15 Novel Small Molecule E3 Ligase Activators as Anti-Inflammatory Agents

Kumar Suresh, PhD, Senior Director, R&D Biology, Progenra, Inc.

In this talk, I will present for the first time discovery and characterization of novel E3 ligase activators that suppress TH2 and TH17 differentiation and exhibit robust anti-inflammatory properties. Nedd4-family E3 ligases, including Itch, negatively regulate inflammatory immune responses by suppressing TH2 and TH17 differentiation and cytokine production. Genetic disruption of Itch leads to the development of multi-system immune disorders and lung inflammation.

11:45 Sponsored Presentation (Opportunity Available)

12:00 pm Targeting TRAF6 E3 Ligase Activity with Small Molecules Combats Chronic Inflammation and Autoimmunity

Kamyar Hadian, PhD, Group Leader, Helmholtz Zentrum München

Constitutive NF-κB signaling represents a hallmark of chronic inflammation and autoimmune diseases. The E3 ligase TRAF6 acts as a key regulator bridging innate immunity, pro-inflammatory cytokines, and antigen receptors to the NF-κB pathway. Here, we present an inhibitor of TRAF6-Ubc13 interaction that reduces TRAF6 activity in vitro and in cells. Importantly, this inhibitor ameliorated inflammation and improved disease outcomes of autoimmune psoriasis and rheumatoid arthritis in preclinical mouse models.

12:30 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:30 Dessert Break in the Exhibit Hall with Poster Awards Announced

Poster Awards Sponsored by Domainex

自然免疫系の標的化

2:15 Chairperson’s Remarks

Daniel Dairaghi, PhD, Senior Research Advisor, Medicinal Chemistry, Eli Lilly & Co.

2:20 Bacterial Mediated Chemical Transformations of Autoimmune Drug Metabolism

Jason Michael Crawford, PhD, Associate Professor, Departments of Chemistry and Microbial Pathogenesis, Yale University

Photorhabdus asymbiotica causes soft tissue infections of the skin. This bacterium produces the immunomodulator tapinarof during its pathogenic phase. Tapinarof is in phase 3 clinical trials to treat the skin disorders psoriasis and atopic dermatitis. We demonstrate that bacteria can transform tapinarof into other novel potent products that activate the pathways associated with clinical efficacy and kill inflammatory bacteria of the skin.

2:50 Presentation to be Announced

3:20 Targeting ROR and Other Nuclear Hormone Receptors: Chemistry Challenges and Beyond

Scott Thacher, PhD, CEO, Orphagen

This presentation will cover the chemistry challenges we’ve faced targeting nuclear hormone receptor for inflammation and cancer. A sub-theme will be “finding the right indication for druggable nuclear receptors.” I will also discuss our second-in-line program for antagonists to steroidogenic factor-1 (NR5A1).

3:50 Networking Refreshment Break

4:20 Presentation to be Announced

4:50 Targeting Soluble TNF to Eliminate Chronic Inflammation without Immunosuppression

RJ Tesi, MD, CEO/CMO, Inmune Bio

INB03 is a selective inhibitor of soluble TNF that is a potent anti-inflammatory agent that is not immunosuppressive. Current drug development leverages that important biology as part of therapy for cancer, neurodegenerative diseases and NASH. INB03 is significantly different from existing non-selective TNF inhibitors that block both soluble TNF (the BAD TNF) and trans-membrane TNF (the GOOD TNF). This difference makes all of the difference in safety, efficacy and therapeutic opportunity.

5:20 GSNOR Inhibitors for Inflammatory, Auto-Immune, and Oxidative Stress Based Diseases: RA, IBD, and NASH

Matthews O. Bradley, PhD, Chairman, President and Founder, SAJE Pharma, LLC

S-nitrosoglutathione Reductase (GSNOR) regulates nitrosylation signal transduction pathways and is over-expressed in many inflammatory human diseases. We identified, using X-ray crystallography and predictive in vitro assays, inhibitors of GSNOR that are potent, selective, orally bioavailable, and safe. The compounds inhibit oxidants, cytokines, chemokines, and inflammatory cells both in vitro and in vivo. The lead compound, SPL-891.1, is active in models of RA, IBD, and NASH among others.

5:50 Close of Conference

* 不測の事態により、事前の予告なしにプログラムが変更される場合があります。