Epigenetic Inhibitor Discovery
A New Frontier in Drug Development
April 23-24, 2014
Within the past few years, an expanding collection of epigenetic modulators - spanning multiple classes and disease implications - have been positioned as promising targets for therapeutic development. Since the approval of first-generation epigenetic therapies, an increasing amount of chemically tractable epigenetic targets, such as Histone Deacetylases (HDACs), Histone Methyltransferases (HMTs), Histone Demethylases (HDMs), and a distinct set of chromatin readers - the BET family bromodomains - have given rise to novel inhibitors that are now in preclinical and clinical development. However, obtaining potent, highly-selective and cell-active inhibitors requires skillful utilization of varied assays and screening methods, such as high-throughput screening (HTS), focused screening, knowledge/fragment-based approaches, and phenotypic assays to efficiently navigate lead discovery of epigenetic targets. Cambridge Healthtech Institute is proud to announce the inaugural Epigenetic Inhibitor Discovery conference, gathering a diverse cross-section of academic and industry leaders actively working on developing epigenetic inhibitors.
Great opportunity to share and discuss cutting-edge approaches/aspects in drug discovery.
Fabrizio G., Principal Scientist, AstraZeneca
7:00 am Registration and Morning Coffee
8:00 Chairperson’s Opening Remarks (Sponsorship Opportunity Available)
8:10 Discovery and Optimization of BET Bromodomain Inhibitors
Brian Albrecht, Ph.D., Senior Director, Medicinal Chemistry, Constellation Pharmaceuticals
The BET bromodomain class of chromatin reading domains have emerged as new and exciting epigenetic targets for the potential treatment of cancer and immunological disorders. Inhibition of these targets leads to profound effects in relevant models of disease. The discovery and optimization of potent and selective BET bromodomain inhibitors will be presented.
8:40 Targeting Epigenetic Readers for Cancer Therapy
Jun Qi, Ph.D., Senior Research Scientist, Medical Oncology, Dana-Farber Cancer Institute
We have recently developed first-in-class, drug-like inhibitors of “bromodomain and extraterminal domain” epigenetic readers (BETs) for mechanistic study and therapeutic application in cancer and other diseases. We are continuously integrating the transcriptional consequences of BETi with changes in the epigenomic landscapes of cancer cells to elucidate the mechanisms underlying response to BETi using chemical and genetic perturbations.
9:10 Cracking the Histone Code: Development of Inhibitors of the Bromodomain-Histone Interaction
Stuart Conway, Ph.D., Associate Professor, Chemistry, University of Oxford
I will describe the development of our published BET bromodomain inhibitors and our unpublished work on the development of potent CREBBP bromodomain inhibitors.
9:40 Coffee Break
10:05 Screening for Inhibitors of Bromodomain 4 … Have We Learned Something? … You BET!
Paul Bonin, Principal Scientist, Assay Development and Pharmacology, Primary Pharmacology Group, Pfizer, Inc.
To identify inhibitors of BRD4, a fluorescence polarization (FP) assay was developed that utilized a version of the novel BET family chemical probe PFI-1 labeled with a Cy5 dye. Binding of this probe to BRD4 as well as other BET family members (BRD2, BRD3, BRDT) was characterized. In addition, the ability of the BRD4 FP assay to identify legitimate fragment library hits will be compared to the ability of other assay technologies including surface plasmon resonance (SPR), time resolved fluorescence resonance energy transfer (TR FRET) and AlphaScreenTM.
10:35 Targeting Bromodomains - The Validity of High-Throughput Virtual Screening in Epigenetic Drug Discovery
Stefan Günther, Ph.D., Professor, Institute of Pharmaceutical Sciences, Pharmaceutical Bioinformatics, University of Freiburg
Bromodomains are acetyl-lysine epigenetic mark reader proteins. Small molecules inhibiting them have potential as anti-inflammatory, antiviral, and anticancer agents. We report the identification of novel scaffolds which potently inhibit specific bromodomains and exhibit antiproliferative activity against leukemia cell lines.
11:05 Sponsored Presentation (Opportunity Available)
11:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
12:05 pm Session Break
1:15 Chairperson’s Remarks
Elisabeth Martinez, Ph.D., Assistant Professor, Pharmacology, University of
Texas Southwestern Medical Center
1:20 Histone Methyltransferase Inhibitors: Fast-Acting Molecules against Blood and Liver Stage Malaria Parasites
Matthew Fuchter, Ph.D., Senior Lecturer, Synthetic and Medicinal Chemistry, Department of Chemistry, Imperial College London
We have pursued natural product and synthetic histone lysine methyltransferase (HKMT) inhibitors as novel therapeutics for malaria. We have identified highly active compounds that produce: rapid, stage- unspecific and irreversible killing of blood stage P. falciparum parasites with comparable potency against resistant strains; rapid activity in vivo; and unprecedented activating activity toward liver stage hypnozoites of P. cynomolgi parasites. Taken together this positions the HKMTs as a highly exciting new target class for the development of novel anti-malarials.
1:50 Discovery and Characterization of a Jumonji Histone Demethylase Inhibitor with in vivo Activity
Elisabeth Martinez, Ph.D., Assistant Professor, Pharmacology, University of Texas Southwestern Medical Center
I will discuss the development of a cell-based assay used in HTS to identify epigenetic modulators of gene expression. Using the small molecule JIB-04 as an example, I will describe the characterization of the mechanism of action of active compounds and their activity in cells and in animal models of disease, particularly in cancer.
2:20 Sponsored Presentation (Opportunity Available)
2:35 Refreshment Break in the Exhibit Hall with Poster Viewing
3:20 Chemical Probes for Histone Demethylases
Xiang Wang, Ph.D., Assistant Professor, Chemistry and Biochemistry, University of Colorado at Boulder
Histone demethylases are the latest class of histone modifying enzymes that have profound impacts on a variety of cellular processes and disease processes. Specific chemical probes are not only important to assist the elucidation of their cellular functions, but also critical to evaluate them as “druggable” targets to treat diseases. We have made and will continue to make significant progress in developing novel probes for both applications.
3:50 Discovery of Histone Lysine Demethylase Inhibitors
Takayoshi Suzuki, Ph.D., Professor, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
As there is increasing evidence that lysine demethylases (KDMs) are associated with various disease states, they have emerged as attractive targets for the development of new therapeutic drugs. We have identified several classes of KDM inhibitors. This presentation will discuss the design, synthesis, and evaluation of our most recent KDM inhibitors and their possibility as anticancer agents will be presented.
4:20 Session Break
» 4:30 Plenary Keynote Presentation
James Wells, Ph.D., Professor, Pharmaceutical Chemistry and Cellular & Molecular Pharmacology, University of California San Francisco
5:30 Welcome Reception in the Exhibit Hall with Poster Viewing
6:30 Close of Day
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