Next-Generation Histone Deacetylase Inhibitors


Cambridge Healthtech Institute 第11届
次世代组织蛋白去乙醯酶抑制剂
新生物学、新化学、新并用疗法

第15届Discovery on Target其中一环

本会议以次世代组织蛋白去乙醯酶抑制剂为主题,解明这个复杂药物标靶家族细胞功能的研究面及临床面进展。另外也安排了互动会议及小组讨论,能够掌握各种机会拓展人脉,在分享崭新想法的同时建立合作关系。

Final Agenda


RECOMMENDED ALL ACCESS PACKAGE:

· September 25 Symposium: Immunomodulatory Small Molecules

· September 25 Short Course: Immunology Basics for Chemists

· September 26-27 Conference: Targeting Histone Methyltransferases and Demethylases

· September 27-28 Conference: Next-Generation Histone Deacetylase Inhibitors

· September 27 Short Course: Impact of Convergence of Immunotherapy and Epigenetics on Drug Discovery

· September 28-29 Symposium: CNS and Neurodegenerative Targets


Wednesday, September 27

11:50 am Conference Registration Open

12:20 pm Plenary Keynote Program

(click here for details)

2:00 Refreshment Break in the Exhibit Hall with Poster Viewing

Insights into Emerging HDAC Biology

2:45 Welcome Remarks

Tanuja Koppal, Ph.D., Conference Director, Cambridge Healthtech Institute

2:50 Chairperson's Opening Remarks

Timothy A. McKinsey, Ph.D., Associate Professor and Associate Division Head for Translational Research, Director, Consortium for Fibrosis Research and Translation, Department of Medicine, Division of Cardiology, University of Colorado Denver

2:55 Photo-Activatable HDAC Inhibitors for Modulating Inflammation

Pamela Chang, Ph.D., Assistant Professor, Department of Microbiology and Immunology, Cornell University

The immune system is an essential component of host defense that is mediated by inflammatory molecules produced by immune cells. These inflammatory mediators are regulated at the transcriptional level by chromatin-modifying enzymes including histone deacetylases (HDACs). Here we describe a strategy to regulate inflammation and immunity with photo-controlled HDAC inhibitors, which can be selectively delivered to target cells by light irradiation to minimize off-target effects.

3:25 HDAC Inhibitors for Non-Oncology Indications: Focus on Heart, Kidney and Fat

Timothy A. McKinsey, Ph.D., Associate Professor and Associate Division Head for Translational Research, Director, Consortium for Fibrosis Research and Translation, Department of Medicine, Division of Cardiology, University of Colorado Denver

Obesity is a major risk factor for the development of diabetes, heart failure and chronic kidney disease. I will discuss our recent findings that suggest novel roles for specific HDAC isoforms in the control of obesity, glucose tolerance and cardiorenal disease, and the potential for isoform-selective HDAC inhibitors for the treatment of heart, kidney and metabolic dysfunction.

3:55 Sponsored Presentation (Opportunity Available)

4:25 Refreshment Break in the Exhibit Hall with Poster Viewing

5:00 Progress in Developing Novel HDACi for the Treatment of Neurodegeneration

Berkley A. Lynch, Ph.D., Senior Director, CNS Research, Rodin Therapeutics

Research supports the role of certain HDAC isoforms in synaptic plasticity, learning and memory, and in neurodegenerative diseases, including Alzheimer's disease. HDAC inhibitors targeting specific HDAC complexes show promise in improving synaptic resilience and treating neurodegenerative diseases. A key clinical challenge is dose-limiting hematological toxicity. Rodin has developed selective HDAC inhibitors that show reduced hematological toxicity while maintaining the ability to enhance synaptic resilience.

5:30 HDAC6 Inhibitors, Autophagy, Mitochondrial Movement, and Disease Modification

Alan P. Kozikowski, Ph.D., Professor, College of Pharmacy, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago; Founder, Actuate Therapeutics Inc.

In this lecture I will present information on the design, synthesis, and testing of ligands that are highly selective for HDAC6 inhibition and show the effects of these compounds in animal models of diseases such as Rett syndrome, Alzheimer's disease, Charcot Marie Tooth disease, cancer, and stroke.

6:00 Drug Safety for Epigenetic Drugs: What Should Be Done?

Kevin S. Sweder, Ph.D., DABT, Director, The Forensic and National Security Sciences Institute, Center for Science & Technology, Syracuse University

The ability of non-genotoxic agents to induce cancer has been documented and a reassessment of testing for environmental and human safety is required. Drug safety testing has relied on genetic toxicology assays designed to detect DNA damage leading to mutation and cancer, which are not suitable for compounds that function through epigenetic changes. How then might we predict long-term downstream effects through epigenetic mechanisms?

6:30 Close of Day

6:30 Dinner Short Course Registration

Click here for details on short courses offered.

Thursday, September 28

7:30 am Registration Open

8:00 Interactive Breakout Discussion Groups with Continental Breakfast

Grab a cup of coffee and join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are available on the conference website.

HDACi for Cancer Immunotherapy and Combination Therapies

9:00 Chairperson's Remarks

Stephen Shuttleworth, Ph.D., COO and CSO, Karus Therapeutics Ltd.

9:05 Epigenetic Targeting of Foxp3+ Treg Cells to Promote Anti-Tumor Immunity

Wayne W. Hancock, M.D., Ph.D., Professor of Pathology and Chief of Transplant Immunology, Children's Hospital of Philadelphia and University of Pennsylvania

HDACs such as HDAC1, HDAC2 and HDAC3 function as part of large multi-molecular complexes. We have begun to study the effects of targeting individual HDACs or co-associated proteins within these complexes. This presentation will deal with our successful targeting of individual members of the CoREST complex during cancer and inflammatory responses.

9:35 Epigenetic Priming with New HDAC Class I Inhibitor 4SC-202 Sensitizes Tumor for Anti-PD-1/PD-L1 Therapy

Svetlana Hamm, Ph.D., Head of Translational Pharmacology, 4SC AG

Epigenetic drugs were shown to increase immunogenicity and recognizibility of tumors by immune cells, and there is growing evidence that combination of epigenetic modulators with different cancer immunotherapies results in increased clinical benefit. We have found that 4SC-202, a new oral HDAC class I inhibitor, modulates inflammatory networks in the tumor microenvironment, strongly increases tumor infiltration with tumoricidal cytotoxic T cells and synergizes with anti-PD1/PD-L1 therapy.

10:05 Improving Cancer Immunotherapy with Selective HDAC Inhibitors

Alejandro Villagra, Ph.D., Assistant Professor, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University

A considerable number of reports have analyzed the role of the specific inhibition of HDACs in cancer as well as processes of immune regulation. This new collection of information has helped the rational design of improved anti-cancer drug candidates to be used as stand-alone or as combination partners in immunotherapeutic approaches. In here, we will discuss the new functional roles of HDAC6 and other HDAC inhibitors as immune regulators in cancer and immune cells, and the new combination strategies being tested to improve immunotherapy.

10:35 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

11:20 Promise of HDAC and IKK Inhibition as Combination Therapy for Solid Tumors

Ivana Vancurova, Ph.D., Professor of Biological Sciences, Department of Biology, Laboratory of Cancer Immunology, St. John's University

We present evidence that may explain the decreased efficacy of HDAC inhibition (HDI) in ovarian cancer (OC), based on our data demonstrating that HDI increases IKK-dependent interleukin-8 expression, which induces OC cell proliferation. Combination of HDI and IKK inhibitors significantly reduces tumor growth in mice, compared to either drug alone, suggesting that IKK inhibitors may increase HDI effectiveness in OC and other solid tumors characterized by increased IL-8 expression.

11:50 Design and Development of KA2507, an Orally-Active HDAC6-Selective Inhibitor with Tumor Immunotherapeutic Activity

Stephen Shuttleworth, Ph.D., COO and CSO, Karus Therapeutics Ltd.

12:20 pm Sponsored Presentation (Opportunity Available)

12:50 Session Break

1:00 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:50 Refreshment Break in the Exhibit Hall with Poster Viewing

Exploiting New Chemistries and Screening Platforms

2:35 Chairperson's Remarks

Ralph Mazitschek, Ph.D., Assistant Professor, Harvard Medical School; Co-Director of the Chemical Biology Platform, Center for Systems Biology, Massachusetts General Hospital

2:40 Non-Catalytic Inhibitors Target the Zinc-Finger Ubiquitin-Binding Domain of HDAC6

Matthieu Schapira, Ph.D., Principal Investigator, Structural Genomics Consortium, University of Toronto

Virtual and fragment-based screens identified a novel class of inhibitors targeting the unique zinc-finger ubiquitin-binding domain of HDAC6. Crystal structures in complex with these screening hits provide a framework for structure-based optimization.

3:10 FEATURED PRESENTATION: Novel Insights about Deacetylation by HDAC6

Patrick Matthias, Ph.D., Senior Group Leader, Friedrich Miescher Institute for Biomedical Research (FMI)

We will present the crystal structure of the two catalytic domains of Histone deacetylase 6 (HDAC6), in complex with the pan-HDAC inhibitor, trichostatin A (TSA) to 1.6Å resolution. The structural backbone of each catalytic domain is highly similar to each other and has overall similarity to other deacetylase domains. We propose a detailed model explaining how HDAC6 can uniquely deacetylate tubulin. We will also discuss the identification of novel substrates and the implications for understanding the activity of this enzyme.

3:40 Session Break

3:55 The Importance of Non-Catalytic Domains of HDAC6 for Interactions with Tubulin

Cyril Barinka, Ph.D., Principal Investigator, Laboratory of Structural Biology, Institute of Biotechnology, Vestec, Czech Republic

We will present data on interactions between human HDAC6 and tubulin/microtubules. By using single-molecule TIRF microscopy we identified structural features governing HDAC6 binding to assembled microtubules. Furthermore, we detailed the influence of HDAC6 on microtubule assembly and dynamics. Our data show that structural motifs beyond the HDAC6 catalytic domains play an important role in HDAC6/tubulin interactions and influence microtubule dynamics.

4:25 Light-Controlled Epigenetics

Ralph Mazitschek, Ph.D., Assistant Professor, Harvard Medical School; Co-Director of the Chemical Biology Platform, Center for Systems Biology, Massachusetts General Hospital

4:55 Close of Conference

* 活动内容有可能不事先告知作更动及调整。

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