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December Meeting
The 928th Meeting of the Northeastern Section of the American Chemical Society

Northeastern Section
American Chemical Society (NESACS)

Symposium EPIGENETIC TARGETS


Organized by the Medicinal Chemistry Section of the Northeastern Section, American Chemical Society

Thursday 13th, 2012 Genzyme Corporation- (Sanofi)


153 Second Avenue, Waltham Massachusetts 02451
Northeastern Conference Room 3.00 pm 3.15 pm Refreshments Welcome Raj (SB) Rajur, NESACS Medicinal Chemistry Program Chair, CreaGen Biosciences, Inc., Woburn, MA Introductory Remarks Norton P. Peet, Director of Chemistry, Microbiotix, Worcester, MA

3.20 pm

3.30pm - 4.15 pm

Ramesh Shivdasani, MD.Ph.D Associate Professor of Medicine, Harvard Medical School DFCI, Boston, MA 02451 Title: "Epigenetics in gastrointestinal differentiation and cancer." William H. Miller, Ph.D Director and Head of Chemistry, Oncology R&D, Cancer Epigenetics DPU GlaxoSmithKline, Collegeville, PA 19426-2990 Title: Discovery of Small Molecule Inhibitors of the Histone Methyltransferase EZH2 Dafydd Owen, Research Fellow, Pfizer Worldwide R&D, Cambridge, MA 02140 Title: Chemical Probes for Epigenetics
Social Hour Dinner Keynote Presentation

4.15pm - 5.00 pm

5.00 pm 5.45 pm

6:00 6.45 pm 6:45 pm 7.45 pm 7:45 pm-8.30 pm

Brian Albrecht, Ph.D Head of Medicinal Chemistry, Constellation Pharmaceuticals, Cambridge, MA 02142 Title: Inhibition of BET Bromodomains for the Treatment of Cancer

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THERE IS NO REGISTRATION FEES TO ATTEND THE SYMPOSIUM: PUBLIC IS INVITED


Dinner reservations should be made no later than noon, Thursday, December 6 , 2102. Reservations are to be made using PayPal: http://acssymposium.com/paypal.html. Select pay with credit or debit card option and follow the additional instructions on the page. Members, $30; Non-members, $35; Retirees, $20; Students, $10. Reservations for new members and for additional information, contact the secretary, Anna Singer, at (781)272-1966 between 9am and 9pm or e-mail at secretary@nesacs.org. Reservations not cancelled at least 24 hours in advance must be paid. Directions to Genzyme-Sanofi Waltham Site
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Use MapQuest for the directions: Address 153 Second Avenue, Waltham Massachusetts 02451

Speakers Bio and Abstracts:


Ramesh Shivdasani, MD. Ph.D Associate Professor of Medicine, Harvard Medical School DFCI, Boston, MA 02451 Title: "Epigenetics in gastrointestinal differentiation and cancer." Abstract: Stable cell states require that the chromatin at lineage-specific genes permit transcription, whereas genes specific to other lineages are silenced. Such states, which are commonly disrupted in cancer, reflect chromatin interactions with lineage-specific transcription factors (TFs), and they can be understood through genome-wide analysis of chromatin marks and TF binding sites. Active genes are typically marked by covalent histone modifications such as H3K4me2 at their promoters and lineage-specific enhancers, and H3K79me2 across the gene body. Using primary tissues from genetically engineered mice and the dynamic intestinal epithelium as a model system, Dr. Shivdasani will discuss the functional requirements for such marks and how they are placed and modulated.
Biographical Sketch:

Ramesh A. Shivdasani, M.D., Ph.D., is a laboratory scientist and Medical Oncologist at the Dana-Farber Cancer Institute, and Associate Professor of Medicine at Harvard Medical School. His laboratory studies stomach and intestinal development and differentiation, specifically, how transcription factors and chromatin respond to few cell-extrinsic signals to induce and maintain epithelial cell fates. A key goal is to understand how normal differentiation mechanisms are subverted in cancer. Dr. Shivdasani has published over 100 peer-reviewed articles and served on numerous governments advisory panels. He is an elected member of the American Society of Clinical Investigation and the Association of American Physicians. . William H. Miller Cancer Epigenetics Discovery Performance Unit, Oncology Research and Development, GlaxoSmithKline Pharmaceuticals, 1250 S. Collegeville Road, Collegeville, PA 19426 Title: Discovery of Small Molecule Inhibitors of the Histone Methyltransferase EZH2 Abstract: EZH2, the catalytic subunit of the polycomb repressive complex 2 (PRC2), is a lysine methyltransferase that catalyzes the methylation of the terminal-NH2 group of histone 3 lysine 27 (H3K27), leading to trimethylation (H3K27me3) and transcriptional silencing of target genes. Several studies show that elevated levels of EZH2 correlate with poor prognosis in solid tumors including prostate, breast, kidney, and lung. In addition, mutations at Y641 and A677 within the catalytic SET domain of EZH2 occur in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma, leading to increased levels of H3K27me3. These findings suggest that dysregulation of H3K27me3, through EZH2 overexpression or point mutations, silences target genes important in tumor growth and survival. This presentation will describe the identification of GSK126, a potent, selective, SAM-competitive, small-molecule inhibitor of EZH2 methyltransferase activity. GSK126 decreases global H3K27me3 levels, reactivates silenced PRC2 target genes, and inhibits the proliferation of EZH2 mutant DLBCL cell lines in vitro and in vivo. These results suggest that small molecule EZH2 inhibitors may be useful for the treatment of EZH2 mutant lymphomas.

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Biographical Sketch: Bill Miller completed his Ph.D in synthetic organic chemistry from Yale university working with Professor Samuel Danishefsky . He then joined professor Yoshito Kishi laboratory at Harvard University as a NIH postdoctoral fellow. His industrial carrier started at Dupont in 1989. In 1991 he Joined SmithKline Beecham . SmithKline Beecham merged with Glaxo Wellcome in 2000 to form GlaxoSmithKline (GSK). Currently bill is serving as the Director and Head of Chemistry in the Cancer Epigenetics DPU at GSK. Dafydd Owen Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Cambridge, MA 02140 Title: Chemical Probes for Epigenetics Abstract: Research into the role of epigenetics in disease could be significantly accelerated if chemical probes for such targets were available that were suitably selective and permeable for cell-based studies. Pfizer is a member of a publicprivate partnership led by the Structural Genomics Consortium (SGC) to help identify a suite of high-quality chemical probes for epigenetic targets. This partnership is unique in that it brings the medicinal chemistry expertise within industry together with biological expertise in academia to drive basic research in an emerging area of important biology of potential relevance to many diseases. Chemical modifications of histones that influence epigenetic regulation include changes such as methylation of lysine/arginine residues and acetylation of lysine residues. A number of epigenetic enzymes have now been identified that either introduce these epigenetic marks (writers) or remove them (erasers). In addition, regulatory proteins have been discovered that directly recognize histone modification status (readers) and drive the localization of complexes which control gene expression. Many of these target classes have little or no chemical matter and Pfizer has committed to discovering and disclosing chemical probes, free from restriction on use to the scientific community for further research and publication. This presentation will describe recent progress in this collaboration and highlight the discovery of novel chemical probes for epigenetic proteins that may have an important future role in disease. Biographical Sketch: Dafydd Owen has thirteen years experience as a medicinal chemist in the design and synthesis of drug-like molecules for Pfizer at its Sandwich UK and Cambridge MA research sites. He obtained his first degree at Imperial College in 1994 before moving to the University of Cambridge to gain a Ph.D under the supervision of Professor Steve Ley in 1997. Having won a research fellowship for postdoctoral work, he spent 1998 with Professor Leo Paquette at Ohio State University. During his research career has delivered over twenty five invited lectures and is also an author on over thirty research papers and patents. He has made contributions to three compounds currently in Pfizers Phase I/II portfolio. In 2009 he was the recipient of a Pfizer Worldwide R&D People Leader Award. In the same year he was selected as an ACS Organic Division Young Industrial Investigator. He currently leads an outward looking, academically collaborative group for Pfizer researching chemical probes for epigenetic targets. Brian Albrecht, Ph.D Head of Medicinal Chemistry, Constellation Pharmaceuticals, Cambridge, MA 02142 Title: Inhibition of BET Bromodomains for the Treatment of Cancer Title: Inhibition of BET Bromodomains for the Treatment of Cancer Abstract: Inhibition of the BET bromodomain family of chromatin readers leads to effective tumor growth inhibition in xenograft models. The discovery and optimization of a series of potent and selective isoxazoloazepine BET inhibitors will be presented.
Biographical Sketch:

Brian joined Constellation Pharmaceuticals in May 2008 as one of the first scientists and is currently a Sr. Director of Medicinal Chemistry. Before joining Constellation, Brian held several positions at Amgen in Cambridge, MA where he worked on a variety of projects in the oncology and neuroscience therapeutic areas. Brian received his BA in Chemistry from Lafayette College in Easton, PA then went on to do doctoral studies at Colorado State University before joining Amgen.

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