IFL

Cambridge Healthtech Institute 第9回

Inflammation and Autoimmune Inhibitors

( 炎症と自己免疫疾患の阻害剤 )

経口投与可能な治療薬の開発に向けた低分子医薬品のアプローチ

2018年4月3-4日 | Hilton Bayfront | カリフォルニア州サンディエゴ

 

 

近年慢性的な炎症や自己免疫疾患など免疫系の障害が、医薬品開発業界の重要な課題となっています。この背景には、こうした症状を抱える患者数の増加という事情に加え、長期的な治療に使用する場合、注射投与される現在の生物製剤やタンパク質ベースの治療薬に比べて患者の利便性が高い経口投与可能な医薬品の開発が可能になっているという事情があり、2013年には、初の経口関節リウマチ治療薬である低分子ヤヌスキナーゼ阻害剤が市場に投入されています。免疫治療の分野で細胞透過性化学薬品の開発を促すもう1つの要因は、免疫学的な経路と疾病の原因となる細胞内の因子に関する知識の大幅な増加です。これらの因子は、生物製剤で標的化可能な対象が限定される細胞表面のタンパク質の数を大幅に上回っています。このカンファレンスプログラムでは、免疫系の障害に対する治療薬の開発に取り組んでいる創薬生物学や化学の研究者が一堂に会して、臨床研究段階へと進む可能性のある薬剤候補についての最新情報を交換し、新たな低分子医薬品に関する医薬品化学分野の取り組みについて議論する予定であり、早期段階の研究が進められている細胞内の免疫系障害や炎症に関連する有望な創薬標的にも光が当てられます。


Final Agenda

4月3日 (火)

7:00 am Registration and Morning Coffee

自己免疫疾患と炎症の治療を目的とした細胞内キナーゼの標的化

8:00 Welcome Remarks
Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

8:05 Chairperson's Opening Remarks

John Robinson, PhD, Director, Medicinal Chemistry, Array Biopharma

8:10 BTK for Lupus and Other Indications: Lead Optimization of a Covalent Inhibitor

Lesley Liu-Bujalski, PhD, Senior Target Chemist, Medicinal Chemistry, EMD Serono

Bruton's tyrosine kinase (Btk) is a promising drug target for the treatment of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). We set out to identify an orally bioavailable, highly selective BTK inhibitor, that might be suitable for the treatment of chronic diseases. Using a combination of X-ray crystallography, wild-type and mutant BTK functional assays, stability studies, and in vivo PK/PD models, lead optimization efforts led to the identification of evobrutinib.

8:40 BTK Covalent Inhibitor for Rheumatoid Arthritis

Matthew D. Linnik, PhD, Senior Research Fellow, Immunology, Lilly Biotechnology Center

I will present preclinical and clinical pharmacology of our covalent inhibitor against BTK that has some cross reactivity to other Tec kinases. It is in Phase II for rheumatoid arthritis. In addition to covering the non-clinical and clinical pharmacology results, my presentation will also address how to study and characterize covalent inhibitors, including distinguishing between pharmaco-kinetics and target occupancy.

9:10 Sponsored Presentation (Opportunity Available)

9:40 Coffee Break

自己免疫疾患と炎症の治療を目的とした細胞内キナーゼおよびGPCRの標的化

10:05 Discovery of Potent and Selective Inhibitors of Receptor-Interacting Protein Kinase 1 (RIPK1) with in vivo Activity

Snahel Patel, PhD, Senior Scientific Manager, Discovery Chemistry, Genentech, Inc.

Regulation of cell death signaling is critical for the maintenance of homeostasis and prevention of disease. A caspase-independent regulated form of cell death called necroptosis is rapidly emerging as an important mediator of a number of human pathologies including inflammatory bowel disease and ischemia reperfusion organ injury. Activation of necroptotic signaling through TNF signaling or organ injury leads to the activation of kinases RIPK1 and RIPK3 and culminates in inflammatory cell death. Here we present the interesting development of potent and selective RIPK1 specific inhibitors that demonstrate protection in a mouse systemic inflammatory response syndrome (SIRS) model.

10:35 Discovery and Optimization of Spleen Tyrosine Kinase Inhibitors for Immunological Diseases

Michael Hoemann, PhD, Senior Scientist, Department of Chemistry, AbbVie, Inc.

This talk will focus on the approach to designing and optimizing a series of Spleen Tyrosine Kinase (Syk) inhibitors. We will highlight the methods used to enhance potency, overcome the challenge of off-target kinase selectivity and optimization of PK properties to yield compounds with in vivo efficacy in the rat CIA model. In addition, the talk will highlight the use of in vitro assays to identify compounds with superior cardiovascular safety profiles.

11:05 Ozanimod (RPC1063), an oral S1P1 and S1P5 modulator, in Relapsing Multiple Sclerosis

Kristen Taylor Meadows, PhD, Principal Scientist, Cell and Molecular Biology, Celgene

Ozanimod, a small molecule S1P1 and S1P5 agonist, demonstrated positive Phase III efficacy with a good safety profile in Relapsing Multiple Sclerosis, an autoimmune disorder targeting myelin within the central nervous system. Ozanimod's primary mechanism of action is to retain lymphocytes in secondary lymphoid tissue. This talk will present data identifying specific peripheral immune populations targeted by ozanimod in preclinical models of MS, and investigate direct effects on resident cells within the central nervous system.

11:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:20 pm Session Break

炎症と自己免疫疾患治療のための新たな標的

1:15 Chairperson's Remarks

Jennifer Venable, PhD, Scientific Director, Medicinal Chemistry, J&J

1:20 NASH and Inflammation: Therapeutic Opportunities in a Complex Disease

Simon Bailey, PhD, MBA, Senior Vice President, Research, Intercept

1:50 Anti-Inflammatory Effects of Non-Bile Acid FXR Agonists in Liver Disease

Bryan Laffitte, PhD, Director, Discovery Pharmacology, Genomics Institute of the Novartis Research Foundation

2:20 The Design of Mechanism-Based Amine Oxidase Inhibitors for the Treatment of Inflammation

Jonathan Foot, PhD, Senior Research Scientist, Drug Discovery, Pharmaxis Ltd.

Amine oxidases are a family of enzymes that catalyze the oxidation of a wide variety of endogenous amines such as collagen or dopamine. They play a key role in oxidative stress, inflammation and protein cross-linking, and in the initiation and progression of fibrosis and cancer. Herein we will present strategies and chemical routes to identify selective amine oxidase inhibitors for the treatment of inflammation-driven diseases.

2:50 Targeting Lipid Mediator, Hepoxilin, for Combatting Inflammation and Inflammatory Bowel Disease

Cecil Robert Pace-Asciak, PhD, Professor, Translational Medicine and Pharmacology, Hospital for Sick Children Research Institute

Findings related to inflammation will be presented for a family of small molecules, Hepoxilins (HX), originally isolated in my laboratory, and of structural analogs (PBTs) that antagonize HX actions in vivo. Results for lung fibrosis and inflammatory bowel disease and enhanced neutrophil migration will be presented and stimulation of neutrophil extracellular trap formation (NETosis). Other promising biological actions will be discussed. It is hoped that interest in this area will allow clinical development.

3:20 Sponsored Presentation (Opportunity Available)

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

4:35 Plenary Keynote Introduction

Kevin Lustig, PhD, CEO, Scientist.com


4:40 PLENARY KEYNOTE: Targeting Ras and MYC for the Treatment of Cancer

Stephen Fesik, PhD, Professor of Biochemistry, Pharmacology, and Chemistry, Orrin H. Ingram II Chair in Cancer Research, Vanderbilt University School of Medicine

Two of the most important targets in cancer are Ras and MYC. However, both of these highly validated cancer targets are thought to be undruggable. In this presentation, I will discuss our approaches for targeting both of these proteins directly and indirectly using fragment-based methods and structure-based design.

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

6:30 End of Day

4月4日 (水)

7:30 am Continental Breakfast Breakout Discussions

ROR核ホルモン受容体を介したIL-17パスウェイの標的化

8:30 Chairperson's Remarks

Bryan Laffitte, PhD, Director, Discovery Pharmacology, Genomics Institute of the Novartis Research Foundation


8:35 FEATURED PRESENTATION: RORC2 Inverse Agonists - Finding Lipophilic Efficiency in a Hydrophobic Pocket

Mark Schnute, PhD, Associate Research Fellow, Medicine Design, Inflammation & Immunology Research, Pfizer

Small molecule, inverse agonists of the nuclear hormone receptor RORC2 are potential therapies for several autoimmune diseases through their ability to inhibit pro-inflammatory cytokine production. This presentation will describe how we have used the key design strategies of optimization of lipophilic efficiency and understanding the interplay of structure, pharmacology and target residence time to advance a high-throughput screening hit into a highly potent, selective and orally bioavailable preclinical development candidate.

9:05 Investigation of Thiazole Bis-Amides as RORγt Inverse Agonists

Kelly McClure, Senior Scientist, Immunology Chemistry, Janssen Research & Development

Differentiation of naive T-cells into IL-17 producing Th17 cells is regulated by the nuclear receptor transcription factor retinoic acid receptor-related orphan receptor γt (RORγt). Blocking the production of pro-inflammatory cytokines by RORγt modulation has the potential to be an effective treatment for autoimmune diseases. Traditional medicinal chemistry approaches have led to the identification of a promising series of thiazole bis-amide RORγt inverse agonists. Optimization efforts leading to the identification of compounds for advanced profiling from this series will be described.

9:35 Coffee Break in the Exhibit Hall with Poster Viewing

10:30 Targeting of RORγ

Daniel J. Cua, PhD, Group Leader, IMR Pathway Biology, Merck Research Laboratories, Palo Alto
I will present our work demonstrating that targeting of RORgamma restrains TCR gene rearrangement and limits development of auto-reactive T cells.

11:00 The Discovery of AZD0284, an Inverse Agonist of Nuclear Receptor RORγt for the Treatment of Psoriasis

Frank Narjes, PhD, Senior Principal Scientist, Medicinal Chemistry, IMED Respiratory, Inflammation & Autoimmunity, AstraZeneca

Retinoic acid receptor-related orphan receptor C2 (RORc2, RORγt, or NR1F3) is essential for the development and differentiation of IL-17 producing TH17 cells, which are important drivers of chronic inflammation in autoimmune diseases such as psoriasis or ankylosing spondylitis. We describe the discovery of our clinical candidate AZD0284, a compound that combines good oral bioavailability with potent suppression of IL-17 production in human TH17 cells, and is currently in Phase I clinical trials.

11:30 Presentation to be Announced

12:00 pm End 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。