IFL

Cambridge Healthtech Institute 第9届

Inflammation and Autoimmune Inhibitors

( 炎症与自体免疫疾病的抑制剂 )

口服药物开发的小分子药物途径

2018年4月3-4日 | Hilton Bayfront | 加州圣地牙哥

 

 

近年来慢性炎症及自体免疫疾病等免疫系统的失调逐渐增加,成为药物开发产业的注目焦点。于此背景之下,再加上患有这些症状的病人数量增加,比起现有生物制剂及蛋白质药物的注射剂,方便的口服药物更适合长期治疗使用,因此开发也如火如荼地展开。在2013年,治疗类风湿性关节炎的第一个口服小分子JAK激酶抑制剂上市了。在免疫治疗领域中促进细胞通透性化学药品开发的原因之一,是因为对免疫学途径与疾病成因的细胞内因子之了解大幅增加,这些因子的数量远远超过生物制剂受限标的的细胞表面蛋白。本研讨会议程将聚集致力于开发免疫系统失调疗法的发现生物学家及化学家,针对具有迈向临床研究阶段潜力的候补药物最新情报进行分享,讨论药物化学领域在最新小分子药物方面的努力,并揭露仍处早期阶段但具有潜力的细胞内免疫及炎症相关药物标的。


Final Agenda

Tuesday, April 3

7:00 am Registration and Morning Coffee

TARGETING INTRACELLULAR KINASES FOR AUTOIMMUNITY AND INFLAMMATION

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

TARGETING INTRACELLULAR KINASES AND GPCRs FOR AUTOIMMUNITY AND INFLAMMATION

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

NEW INFLAMMATION AND AUTOIMMUNITY TARGETS

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

Wednesday, April 4

7:30 am Continental Breakfast Breakout Discussions

TARGETING THE IL17 PATHWAY VIA ROR NUCLEAR HORMONE RECEPTORS

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

* 活动内容有可能不事先告知作更动及调整。