8:30 Chairperson’s Remarks
Paul A. Marks, M.D., President Emeritus and Member, Memorial Sloan-Kettering Cancer Center, Cell Biology Program

8:40 Histone Deacetylase Inhibitors: Bench to Bedside
Thomas A. Miller, Ph.D., Merck Research Laboratories, Boston
HDAC inhibitor lead structures have provided effective platforms for structural optimization, affording HDAC inhibitors with sub-nanomolar HDAC enzyme inhibitory activities. Hydroxamic acids constitute the largest chemical class of HDAC inhibitors and these agents are among the most potent HDAC inhibitors known. The discovery and development of Zolinza™ (SAHA, vorinostat), a novel hydroxamic acid derived HDAC inhibitor, along with relevant background and recent advances in HDAC inhibitor design, will be presented.

9:10 Romidepsin: Maximizing the Potential of a Novel HDAC Inhibitor
Mitchell Keegan, Ph.D., Senior Director, Drug Development, Gloucester Pharmaceuticals, Inc.
Histone deacetylase inhibitors (HDACi) are an exciting drug class with significant clinical activity in T-cell lymphomas. The potential of HDACi in the broader oncology setting remains largely unrealized at this time but continues to be the focus of aggressive development efforts in both industry and academic settings. An overview of Gloucester Pharmaceuticals’ clinical development experience with romidepsin (FK228, depsipeptide) will be presented. Specific topics to be addressed include differences between romidepsin - a natural HDACi - and synthetic products, the impact of "pan-HDAC" activity, and the open question of correlating histone acetylation and clinical response.

9:40 MGCD0103, A Novel HDAC Inhibitor: From Bench to Clinic
Robert Martell, M.D., Ph.D., Chief Medical Officer, MethylGene Inc.
MethylGene has developed an extensive library of HDAC inhibitors. This has allowed development of a spectrum of isotype-selective HDAC inhibitors that have distinct biologic effects. Our goal is to exploit these focused effects, with better therapeutic index, on the wide variety of diseases where epigenetic changes have been described. MGCD0103 is an oral benzamide-based inhibitor, with specific optimization toward activity in cancer. This molecule exhibits broad preclinical activity, including synergy with a variety of other anticancer agents. MGCD0103 is orally available with a half-life of 10 hours and prolonged pharmacodynamic enhancement of histone acetylation and inhibition HDAC activity. Promising clinical activity has been observed in a variety of hematologic malignancies, including Hodgkin’s lymphoma, myelodysplastic syndrome and acute myelogenous leukemia. Clinical development in solid malignancies is underway.

10:30 Belinostat: A pan-HDAC Inhibitor for Treatment of Solid and Hematologic Cancers
Henri Lichenstein, Ph.D., Vice President, Product Development, Curagen Corporation
Histone deacetylase (HDAC) inhibition has emerged as an exciting new approach to treat cancer. Mechanistically, HDAC inhibition leads to inhibition of the cell cycle and induction of apoptosis in cancer cells. Belinostat is a novel small molecule pan HDAC inhibitor of the sulfonamide hydroxamate chemical family. Belinostat has potent (sub to low mM) growth-inhibitory activity on a wide variety of cancer cell types in vitro and has shown anti-tumor activity in animal cancer models. When used in combination therapy with a variety of chemotherapeutics, belinostat has shown additive to synergistic activity in both in vitro and in vivo cancer model systems. Clinical development of belinostat is progressing in a number of Phase IB/II and Phase II studies in solid and hematologic tumor populations.

11:10 Histone Deacetylase Inhibitors: Molecular Mechanism of Action
Paul A. Marks, M.D.
Histone deacetylase inhibitors (HDACi) are a new class of targeted antitumor agents that have shown anti-cancer activities in a wide spectrum of human cancers at well-tolerated doses. HDACi have been discovered that belong to structurally diverse chemical groups including hydroxamates, cyclic peptides, aliphatic acids and benzamides. Inhibitors of HDACs can cause the accumulation of acetylation of histones and many non-histone proteins- altering the structure and function of these proteins. These proteins are involved in regulation of gene transcription, cell proliferation and differentiation, angiogenesis, and cell death pathways including apoptosis, autophagic cell death, mitotic catastrophe and senescence. The targets of these inhibitors can be more properly designated "deacetylases." The deacetylase inhibitors are additive or synergistic with many other antitumor agents. Suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) is the first of the new deacetylase inhibitors to be approved by Food and Drug Administration for therapy of a cancer, cutaneous T-cell lymphoma. Currently, over 70 clinical trials are in progress with HDACi as monotherapy or in combination therapy for many different cancers. This review focuses on the multiple biological pathways that can be altered by HDACi and, as a consequence, lead to death of transformed cells, while normal cells are relatively resistant to inhibitor-induced cell death.

11:40 Development of Biomarkers for Clinical Advancement of Broad-Spectrum and Isoform-Selective HDAC Inhibitors
Sriram Balasubramanian, Ph.D., Director, Translational Research, Pharmacyclics, Inc.
We have developed novel broad-spectrum (PCI-24781) and isoform-selective (PCI-34051) inhibitors of histone deacetylase (HDAC) enzymes, which are in clinical and preclinical development respectively. An efficient strategy for advancement of these compounds requires targeting the best clinical indication, the patient population most likely to respond within these indications, and an optimal dose schedule based upon a clear understanding of the pharmacology and mechanism of action. This talk will summarize the work at Pharmacyclics in each of these areas. To determine relevant tumor types, we have identified novel PD markers that could be used to determine dosage in the clinic, and combined these with classical WBA studies to identify the most responsive tissues in animal models. In the selected tumor types, we have developed markers of resistance and sensitivity from ex-vivo tumors studies that will enable patient stratification in Phase IIb/III. Finally, we have used these PD and efficacy markers to investigate PK/PD relationships in preclinical models and derive dose schedules to be tested in the clinic.

12:10 pm Pharmacological Properties and Biomarker Strategies for the Development of 2nd Generation HDAC Inhibitors
Thomas Beckers, Ph.D Chief Scientific Officer Oncotest GmbH 
Histone deacetylases (HDACs) are lysine specific protein deacetylases, regulating reversible protein acetylation in cells. Inhibitors of class I and II HDACs belonging to different chemical classes are currently in clinical development, including the benzamide analogs MS275 and MGCD0103 as well as the hydroxamate analogs SAHA and LBH-589, In the lecture, in vitro and in vivo data on MS275 / MGCD0103 and SAHA / LBH589 as advanced HDAC inhibitors are presented. In the first part of the lecture, data on inhibition of HDAC isoenzymes in biochemical assays, cytotoxicity profile and reversibility of HDAC inhibitor action and finally whole genome transcriptional analysis of tissue and tumor samples derived from HDAC inhibitor treated nude mice are presented. The second part of the lecture focuses on the HDAC isoenzyme selective analogs MS275 and MGCD0103. Cell cycle studies showed distinct features: cells were transiently arrested in the G1 phase by MS275, but transiently arrested in the M-phase by MGCD0103. Data on the induction of histone S10 phosphorylation and alterations of chromatin structures are presented as well. We finally conclude, that MGCD0103 and MS275 display different cellular profiles that might not been solely explained by their HDAC inhibition profile. In the last part of the lecture, an assay based on the direct measurement of HDAC enzymatic activity as well as the identification and validation of transcriptional markers for HDAC inhibitor action in human peripheral blood mononuclear cells (PBMC) and whole human blood are presented. The cellular HDAC enzymatic activity assay is based on the lysine mimetic substrate Boc-K(Ac)-AMC, allowing quantitative measurement of HDAC activity in human PBMC and whole blood. Using Affymetrix U133plus v2.0 DNA arrays, genes repressed or induced in human PBMC by HDAC inhibitor treatment were identified. Potential transcriptional marker genes were selected, uniformously repressed or induced at highly statistically significant levels by all compounds. Using a qPCR based analysis, a clear concentration-dependent gene induction or repression could be shown with low variability between different donors. EC50 values correlated nicely with IC50 values derived from the HDAC enzymatic activity assay. Both strategies will be evaluated in an on-going clinical trial with an ALTANA proprietary HDAC inhibitor.

5:30 Development of HDAC Inhibitors for CNS Indications
Holger Patzke, Ph.D., Senior Drug Discovery - Neuropharmacology, EnVivo Pharmaceuticals, Inc.

6:00 Happy Hour in the Exhibit Hall

7:30 End of Conference Day

Wednesday, October 17

7:30 am Registration, Morning Coffee & Roundtable Discussion Sessions (Continental Breakfast Served)

Topic: HDAC Inhibitors and Drug Selectivity Issues Moderator: Thomas A. Miller, Ph.D., Merck Research Laboratories, Boston Topic: HDAC Inhibitors and Cardiac Safety • Are cardiac abnormalities a class effect? • Are cardiac safety issues creating a perception problem? Moderator: To Be Announced

8:30 Keynote Introduction (Sponsorship Available)ll

Plenary Keynote Session DELIVERING DRUGS FOR DIFFICULT TARGETS 8:30am Keynote Introduction (Sponsorship Available) 8:40-9:40 Executive Panel: Delivering Drugs for Difficult Targets Executive Panelists: Mikael Dolsten, Ph.D., Executive Vice President, Pharma Research, Boehringer Ingelheim Pharmaceuticals, Inc. Alexander Rod MacKenzie, Senior Vice President, Head of Worldwide Discovery Research, Pfizer Inc. Lex Van der Ploeg, Vice President, Basic Research, Merck Research Laboratories John J. Rossi, Ph.D., Lidow Family Research Chair, Professor, Division of Molecular Biology, Dean, Graduate School of Biological Sciences, Beckman Research Int. of City of Hope Shama Kajiji, Ph.D., MBA, Senior Director, Portfolio Franchise Management Department, Merck and Co. Jesus "Tito" Gonzalez, Ph.D., Senior Director, Biology, Vertex Pharmaceuticals Inc.   Panel Topics: Balancing the R&D Portfolio – Focus or Diversify? Translating Innovation into R&D Productivity Partnering with Biotech & Academia Accelerating Discovery & Development Success through; Investigating More Innovative Targets Improving the Quality of Validated Targets Improving Lead Generation & Optimization Employing Enabling Technologies

9:40 Networking Coffee Break in the Exhibit Hall