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Medicinal Chemistry Group

An Integrated Platform for DUB Inhibitor Discovery

By Sara Buhrlage, Dana-Farber Cancer Institute

Organized by the Medicinal Chemistry Section
of the Northeastern Section, American Chemical Society (NESACS)
Thursday – March 18th, 2021
4:00 pm
Register for the March Webinar meeting here:
Ed Ha
Sara Buhrlage
Assistant Professor, Dana-Farber Cancer Institute

Abstract: DUBs, through cleavage of the isopeptide bond linking ubiquitin and ubiquitin-like proteins to substrates, play a key role in proteolysis as well as localization, interactome and activation of diverse proteins. Increasingly, links between DUBs and disease are being discovered, with perhaps the most excitement around the promise of precision degradation of pathogenic proteins via DUB inhibition. Concomitant with appreciation of the role of DUBs in disease, is a need for high quality chemical probes to study DUB function and pharmacologically validate members of the enzyme family as disease targets. My lab has established a platform for discovery, optimization and rigorous characterization of DUB inhibitors. Our platform integrates DUB library synthesis, medicinal chemistry, biochemistry, high-throughput screening, chemoproteomics, chemical genomics, structural biology, target validation and cancer biology. I will describe our platform including generation of DUB-focused libraries, show how the platform has enabled rapid access to hits, leads and probes for DUBs, and present our work using first-in-class probes to study DUB biology in both biased and unbiased fashions.

Bio: Sara Buhrlage, PhD, is an Assistant Professor in Dana-Farber’s Cancer Biology Department and Harvard Medical School’s Biological Chemistry and Molecular Pharmacology Department. Her research group focuses on the development of first-in-class inhibitors and prototype drugs for deubiquitylating enzymes (DUBs) that can be utilized to pharmacologically validate members of the gene family as new targets for cancer treatment and other diseases. DUBs have garnered significant attention recently as potential therapeutic targets in the field of oncology due to their removal of degradative ubiquitin marks from cancer causing proteins.

Prior to joining as a faculty member in July 2015, Dr. Buhrlage was a professional track scientist at Dana-Farber in the medicinal chemistry core laboratory. In this role she collaborated with Institute researchers to pharmacologically validate novel targets of disease and study mechanisms of oncogenesis and drug resistance.

Dr. Buhrlage completed a Doctor of Philosophy in organic chemistry in 2008, under the direction of Professor Anna Mapp, PhD, from the University of Michigan, where she successfully designed, synthesized and characterized small molecules that bind the transcriptional co-activator CBP and upregulate transcription when tethered to DNA. Following completion of her Doctor of Philosophy, Dr. Buhrlage trained for two years in medicinal chemistry at the Broad Institute
Symposium Organizing Committee: Brian Aquila, Mark Ashwell, Scott Edmondson, Dan Elbaum, Jeremy Green, Paul Greenspan, Adrian Hobson, Blaise Lippa, Lisa Marcaurelle, Min Lu, Kap-Sun Yeung, Andrew Scholte, Mala Gopalsamy, Raj (SB) Rajur (Chair)

Our Mission
The mission of the medicinal chemistry group is to advance knowledge and understanding of drug discovery research by organizing world class quality symposia.
Our meetings provide our attendees with access to top quality science presenters and offer unique networking connectivity with thought leaders in the scientific community.
Our members work at the forefront of the life science sector and are constantly striving to bring new medicines and therapies forward to the clinic to meet unmet need.

Volunteer Opportunities
The Medicinal chemistry group will be interested in volunteers to assist with annual symposium specifically for contacting potential vendors and fund-raising efforts. Please contact the med chem chair, Raj Rajur at, if interested.

Who are we?
  Dr. Raj (SB) Rajur, Chair
  CreaGen Inc.
  Andrew Scholte
  Daniel Elbaum
  Mala Gopalsamy
  Jeremy Green
  Blaise Lippa
  Morphic Therapeutic
  Adrian Hobson
  Brian Aquila
  Scott Edmondson
  Nimbus Therapeutics
  Paul Greenspan
  Min Lu
  Lisa Marcaurelle
  Kap-Sun Yeung
  Bristol-Meyers Squibb
Mark Ashwell    
  Mark Ashwell
  Nimbus Therapeutics

Medicinal Chemistry Webinar Series for the Year 2020
By Paul Greenspan, Takeda Oncology Cambridge, Cambridge, MA 02139
Last winter (which seems like a lifetime ago), the NESACS medicinal chemistry seminar committee was putting the final touches on preparations for our annual “Advances in Chemical Sciences” symposium, which was scheduled for May 2020. When March rolled around, however, everything changed. It became apparent that the COVID-19 pandemic would make it impossible to hold a large indoor event in the intended time frame. We initially considered delaying until later in the year, but it soon became clear that there was just too much uncertainty to give us a high level of confidence in our ability to stage the symposium even in late 2020. (Subsequent events, as we all know, have validated our concerns!)
Despite our disappointment, the committee was determined to find a way to bring high-quality presentations to the local medicinal and organic chemistry community. We quickly settled on a monthly webinar series, with one seminar for each session. Rather than charging for attendance, we’d do it for free! We chose to hold each seminar on the 2nd Thursday of the month, at 4 pm.
We were thrilled when Derek Lowe (Novartis) agreed to be our very first speaker. Derek’s long-running “In the Pipeline” blog has become required reading for anyone looking for in-depth yet highly accessible analysis of the latest scientific COVID news. Derek’s presentation on September 10th, entitled “Coronavirus Therapies: What’s Probably Coming, and What Probably Isn’t”, did not disappoint. He provided an outstanding high-level overview of the current state of the COVID-19 treatment and vaccine landscape, which concluded with a robust Q+A which lasted for over 30 minutes! And perhaps best of all, we had no technical issues!! (Special thanks go to Casi Leal from Sanofi, for her support and guidance on the optimal use of the Zoom webinar platform.)
Our second seminar speaker, on October 8th, was Rebecca Ruck (Merck), who presented “Enabling Technologies for the Development of Best Process.” She highlighted how her teams were able to generate efficient and green process chemistry synthesis routes for 3 key compounds in Merck’s development pipeline. She incorporated scientific successes in hot areas like biocatalysis, traditional catalysis, and flow chemistry and showed how Merck thinks about both cost-of-goods as well as environmental sustainability.
For our 3rd webinar, Atwood Cheung (Novartis) presented the medicinal chemistry story behind the identification of Icenticaftor, a novel potentiator of the cystic fibrosis CFTR Channel, with a focus on its use as a treatment for COPD.
Most recently, Nathan Fuller from Alkermes described his team’s success in identification of selective dual HDAC 1/2 inhibitors. A fascinating aspect of the presentation was the ability of the highlighted compounds to inhibit the HDAC’s only in the context of the CoREST complex, which distinguishes these compounds from other known HDAC inhibitors.
The series has now hit its stride, and we have an exciting series of diverse webinars planned through next spring. Planned speakers are Brian Lanman from Amgen (January 21st), Ed Ha from Angiex (February 11th), Sara Buhrlage from Dana-Farber Cancer Institute (March 11th), and Matthew Clark from X-Chem (May 13th).
As rewarding and successful as thiswebinar series has been, the committee has its attention focused on a return to an in-person symposium in the coming year. We have now targeted Nov. 5th, 2021 for our 10th annual “Advances in Chemical Sciences” symposium, (hopefully sufficient time for vaccination and herd immunity to take hold), and we’re in the process of building an outstanding lineup of speakers, to make up for our lost opportunity in 2020. We are looking forward to seeing everyone in person next year for what will be a truly momentous event! Until then, keep checking this page for more details about the ongoing webinar series?