Chemistry Biology Interface Training Grant Symposium Recap

Chemistry-Biology Interface Training Grant Symposium

Wednesday, May 25, 2011

University of Minnesota, Mayo Auditorium

The Chemistry Biology Interface Training Grant Symposium is held annually as part of the University of Minnesota's NIH-funded grant of the same name. The day's events included a midday poster session and mix of external and internal speakers, including a grant trainee.


Mark Distefano opened the morning with introductory remarks before the first speaker, Rami Hannoush from Genentech. His talk, "Chemical Probes for Inhibiting Wnt Signaling and Visualizing Protein Fatty Acylation," was focused on two subjects. The first part was centered around his work on studying protein-protein interactions and assembly of Wnt signaling complexes in order to discover drugs that interrupt Wnt signaling for cancer. Switching gears, Rami then presented research on the use of fatty acid analogs for imaging protein modification by lipids. This was a fantastic talk that demonstrated the power of new methods for the design of biological probes useful in drug discovery.

Rami Hannoush (Genentech) with Professor Yusuf Abul-Hajj.

Click picture to see more photos from the symposium.

Next up was Leah Randles, a fifth year graduate student and 2007–2009 grant trainee from Kylie Walters' lab, with her talk "Regulation of the Proteasomal Ubiquitin Receptor Rpn13." She presented a lot of intriguing work on using various NMR solution structures to study the role of hPLIC2 as a negative regulator of Rpn13 activity. Leah fielded a lot of questions and spoke with many people about her findings after the talk.


Over 30 posters were presented over lunch in the lobby of Mayo Auditorium. There were a lot of outstanding posters, and much discussion ensued amongst the participants during the 90 minute session.

Intense studying at the poster session.

Click picture to see more photos from the symposium.

Following lunch and the poster session was Professor Adrian Hegeman from the Department of Horticultural Sciences at Minnesota with a presentation entitled "Plant Metabolomics Methodology: Using in Vivo Stable-Isotope Labeling for Elemental Composition Assignments." I was unfamiliar with his work, so this talk was a fascinating insight as to how plant metabolomics can be used to study plant behavior and production of nutrients and responses to stress.


Joseph Beckman from Oregon State University then provided a thought-provoking talk on peroxynitrite, superoxide dismutase (SOD), and amyotrophic lateral sclerosis (ALS) titled "Oxidative Stress and the Chemical Biology of Neurodegeneration: Did Free Radicals Kill Lou Gehrig?" Much of the talk focused on post-translational modification of proteins by nitration of tyrosine residues and evidence that mutations to SOD are involved in ALS. The role of nitration in the regulation of protein function, particularly Hsp90, was also presented.


I unfortunately had to miss the final lecture of day delivered by Leona Samson from MIT on "Complex Biological Responses to DNA Damage." The entire event was a wonderful learning experience, and the organizing committee did an exceptional job of delivering a fantastic program that reflects the diversity and importance of chemical biology research.

Neal Rosen Seminar Recap

Neal Rosen, Enid A. Haupt Chair in Medical Oncology at the Memorial Sloan–Kettering Cancer Center, visited Minnesota on May 18 to present the keynote lecture at the Masonic Cancer Center Research Symposium in the Great Hall of Coffman Memorial Union. Due to conflicting meetings, I could not attend the rest of the Symposium, so my comments are limited to Dr. Rosen's talk. Doug Yee, Director of the Masonic Cancer Center and a former postdoc in Neal's lab, gave him a warm introduction to the assembled crowd.


The title of Neal's presentation was "Feedback Regulation of PI3K-Signaling Pathways–Biologic and Therapeutic Implications." The main theme of the talk was what he calls adaptive resistance of cancers to oncoprotein inhibition by small molecule drugs. He presented data with MAPK and AKT kinase inhibitors to show that inhibition of these oncoproteins relieves upstream feedback inhibition and can attenuate the effects of therapy resulting in oncogene addition - sustained negative feedback throughout the signaling network.

Dr. Rosen takes a question from the crowd

A couple points about the choice of drugs to study were made. First, Neal made the point that drugs are the best way to understand adaption to pathways since this can't be done with siRNA. Second, allosteric kinase inhibitors are preferred, presumably due to issues related to target selectivity. He also related key reasons why effects of a drug can be limited in humans: poor patient selection, suboptimal drug, inadequate pathway inhibition, and adaptive resistance.


Neal closed the talk with a proposal for the design of clinical experiments with oncoprotein inhibitors. A four-step treatment process was proposed with the goal of maximizing tumor cell death:
1. Biopsy the patient's tumor and determine the driver mutation.
2. Treat the patient with an inhibitor of the driver protein at the maximal tolerated dose for x hours.
3. Re-biopsy the tumor and determine its mechanism of adaptation
4. Treat the patient with the driver inhibitor and an inhibitor of the putative dominant driver of the adaption.


This was an informative presentation that captured the interest of both basic and clinical scientists in the audience. Although most of the data was published, Neal put forth some provocative ideas that are sure to spark discussion within the oncology community.

LesFest Recap, Part 2

2011 Lester A. Mitscher Symposium

May 12–14, 2011

Lawrence, KS

University of Kansas, Pharmacy Building and Oread Hotel

Celebrating Professor Mitscher’s 80th birthday and his contributions to the field of medicinal chemistry and to the University of Kansas

Part 1 of my LesFest recap can be read here.

The symposium to honor Les was held on Friday, May 13th in the beautiful new Pharmacy Building on West Campus. Dan Flynn chaired the morning session, which featured talks by me, Steven Djuric, and Dale Boger. Barbara Timmerman (University Distinguished Professor and Chair of the Department of Medicinal Chemistry), Ken Audus (Dean, School of Pharmacy), and Bernadette Gray-Little (Chancellor, University of Kansas) opened the proceedings with some warm, kind words about Les and his lasting contributions to the Department, School of Pharmacy, and University.

The Mitscher Symposium speakers (l–r): Dale Boger, Robert Fecik, Ashok Bhatia, George Ellestad, Les Mitscher, Dan Flynn, Gunda Georg, and Stevan Djuric.

Click on the picture to see more photos from the Mitscher Symposium.

I had the challenging task of giving the first scientific talk of the day, and chose to start my talk with some person reflections about Les and my time at Kansas. I’ll share some of those comments at the end of this post. I was feeling a bit under the weather and my voice was rough, but I thought the talk about some aspects our tubulysin project went very well. The feedback I received was overwhelmingly positive, and I got a lot of excellent suggestions and ideas from members of the audience.

Stevan Djuric from Abbott was up next, and he gave a very interesting talk on new chemistry technologies and methods he and his team have developed. It was a very insightful and thought-provoking presentation about the technological innovations taking place in industry. Stevan is a close friend of Les’ from their many years working together during Les’ consulting.

My postdoc mentor, Dale Boger (Scripps), closed out the morning session with great talk about the amazing chemistry developed for the total synthesis of Vinca alkaloids. This was an updated version of the talk he gave at last year’s National Medicinal Chemistry Symposium, and it included some new vinblastine analogs and biological data. It’s incredible work, and Dale always gives a fabulous presentation. Les hired Dale at Kansas while he was Chair, and Dale recounted some outstanding advice he received from Les while a junior faculty member.

Over lunch I had a enjoyable time catching up with my old friend Tim Caldwell, a former student of Gary Grunewald’s who is now at Deciphera Pharmaceuticals. The time passed quickly, and I had to get back to prepare for the afternoon session.

I had the pleasure of introducing the afternoon speakers, beginning with Dan Flynn, President and CEO of Deciphera Pharmaceuticals, who received his Ph.D. with Les in 1981. Dan’s had an amazing career in pharma, so it’s no surprise that he’s had incredible success with Deciphera, the company he founded in 2003. He presented the ingenious “switch control inhibitor” approach towards the design of kinase inhibitors, which has resulted in an Abl kinase inhibitor that entered a Phase I clinical trial last year. This is amazing work, and Dan had presented a version of this talk a couple months ago here at Minnesota.

George Ellestad was hired by Les at Lederle in 1964, and this launched his remarkable, nearly 40-year career at Lederle and Wyeth. He conducted seminal natural products chemistry through his career, including contributions that led to the development of tigecycline, a glycylcycline tetracycline antibiotic. George is also a Member of the American Chemical Society Division of Medicinal Chemistry Hall of Fame, in part for his ground-breaking work on the identification and mechanism of action of calicheamicin, an enediyne antitumor antibiotic. This lead to the development of Mylotarg, a calicheamicin–antibody conjugate, that was the first drug–antibody conjugate approved for clinical use. Since 2005 George has been an Adjunct Senior Research Chemist at Columbia University. In his talk, George gave a fascinating recount of the structure elucidation, mechanistic studies, and bioconjugate chemistry that ultimately led to the discovery of Mylotarg.

Ashok Bhatia from the Process R&D group at Abbott was up next. Ashok also received his Ph.D. with Les in 1981, and has had a very successful and productive career at Bouroughs–Wellcome and Abbott. Today he spoke about the development of a couple pilot-scale routes to an H3-receptor antagonist, which included some interesting metal-catalyzed cross-coupling chemistry. Process chemistry talks are always fascinating to me, and Ashok’s presentation was extremely insightful.

Although the end of a long day was approaching, it’s always a pleasure to hear about the latest work from Gunda Georg, Chair of Medicinal Chemistry at Minnesota. Les hired Gunda at Kansas in 1984, and we were fortunate to lure her here to Minnesota in 2007. Gunda also relayed advice she received from Les early in her career prior to delving into a two-part talk. The first part described the discovery of minnelide, a triptolide prodrug that is scheduled to begin a Phase I clinical trial later this year. In the second half, she presented enaminone methodology that been used for the total synthesis of tyloindicine alkaloids and analogs. Her talk ended a fantastic day of talks, and all presentations were very well-received.

At the conclusion of the talks, a poster session was held in the lobby of the Pharmacy Building. Twenty posters were presented, including ones by my students, Mike Peterson, Will Fiers, and Yang Li. The poster session was cut a little bit short due to the length of the oral presentations, but everyone stuck around to visit the posters for a while.

The festivities then moved over to the Oread Hotel for a banquet dinner. The food was among the best I’ve ever had at a banquet, and a social hour provided ample time to meet many people I hadn’t had a chance to visit with up to this point. After dinner, the highlight of the evening was a slide show by Les, during which he recounted many stories about his family, research, friends, and travel throughout his career. It was emotional at times, especially when talking about family, and the presentation was both heart-warming and inspirational. This was followed by some words from Les’ sons who talked about their views in growing up in the Mitscher household and how much Dad and Mom mean to them. It was a fitting end to an wonderful evening, and it was hard not to be overwhelmed by the outpouring of love and affection shown to Les by everyone. After everyone had left, my students and I visited with several of the KU students for a while before calling it a night.

Robert Fecik, Les Mitscher, and Pratik Devasthale at the Mitscher house.

Click on the picture to see more photos from the Mitscher Symposium.

The next day, Saturday, Les and his wife, Betty, hosted the out of town guests at their home for an informal open house around noon. It was a relaxed atmosphere, and it gave everyone the opportunity to visit with each other once more before departing Lawrence. There were simply too many great people I met and caught up with to mention everyone by name, but one personal highlight was finally meeting Pratik Devasthale. Pratik received his Ph.D. with Les, and I took over his thesis work on quinolone antimicrobials when I joined Les’ group. He has since gone on to do great work at BMS, most notably the discovery of muraglitazar (Pargluva), a dual alpha/gamma-PPAR agonist for type 2 diabetes that was submitted for marketing approval to the FDA but was ultimately never approved for a variety of factors. After giving my thanks and best wishes to Les and Betty, I picked up my students at the hotel and we hit the road for a rainy drive back to Minneapolis.

I know that everyone has the most profound respect and admiration for their graduate advisor, but my feelings for Les extend far beyond this. Each person that I spoke with over these three days had their own stories of Les’ generosity and thoughtful advice that further cemented Les’ reputation as a great man and scientist. I’ll forever be grateful for all that he taught me; things that still inspire and motivate me today.

Seminars This Week

There’s a couple events of interest this week. The 2011 Research Symposium of the Masonic Cancer Center will be held from 9–3:30 this Wednesday, May 18 at the Great Hall in Coffman Memorial Union. This annual symposium highlights the breadth of great work going on here at the cancer center, and this year is no exception. Neal Rosen from the Memorial Sloan-Kettering Cancer Center kicks things off with the keynote address, "Oncoprotein-feedback Inhibition of Signaling—Biologic and Therapeutic Implications", at 9:30, followed by a poster session and lunch. The afternoon session features researchers from Minnesota, including one by our medicinal chemistry colleague, Chengguo Xing, who will be presenting a talk entitled “An Anticancer Drug Candidate against Drug-resistant Leukemia and Its Potential Mechanism of Action.” You can view the entire agenda here.

On Friday and Saturday, May 20 and 21, I’m delighted to be hosting my collaborator and friend, David Sherman (University of Michigan), in the Department of Chemistry for the Abbott Workshop in Synthetic Organic Medicinal Chemistry. David is world-renowned for his work in studying natural product biosynthesis, combinatorial biosynthesis, and metabolic engineering. David’s lecture, “Novel Drug Leads from Natural Products and their Derivation from Microbial and Biosynthetic Diversity”, will be held at 4:15 on Friday, May 20 in 331 Smith Hall. The more informal workshop session will be held from 10–12:30 on Saturday, May 21 in 117/119 Smith Hall.

LesFest Recap, Part 1

2011 Lester A. Mitscher Symposium

May 12–14, 2011

Lawrence, KS

University of Kansas, Pharmacy Building and Oread Hotel

Celebrating Professor Mitscher’s 80th birthday and his contributions to the field of medicinal chemistry and to the University of Kansas

Lester A. Mitscher

It’s hard to overstate the personal and scientific impact that Les Mitscher has had on medicinal chemistry and his students and postdocs during his nearly 45 years in academia. Affectionately dubbed “LesFest”, the Mitscher Symposium brought together former colleagues and group members from throughout Les’ long career to celebrate his 80th birthday and appointment as Emeritus Professor at the University of Kansas. The main events over the three-day program were a welcoming reception, a day-long symposium, and a banquet dinner.

The Organizing Committee for the event consisted of Dan Flynn (Ph.D. 1981, President and CEO, Deciphera Pharmaceuticals), Barbara Timmerman (Kansas), Brian Blagg (Kansas), and me (Ph.D. 1999, Minnesota), although Dan and his assistant, Anjanette Wilheim, did most of the work. Many others assisted with the planning, and everyone’s help is gratefully acknowledged. An amazing cast of plenary speakers spoke at the symposium: Stevan Djuric (Abbott Laboratories), Dale Boger (The Scripps Research Institute), Dan Flynn, George Ellestad (Columbia University), Ashok Bhatia (Abbott Laboratories), Gunda Georg (University of Minnesota), and me.

In Part 1 of my LesFest review, I’ll first summarize the impressive career and accomplishments of Les, then provide my thoughts about the welcoming reception on Thursday evening. In Part 2, I will review the oral presentations and banquet.

Les was one of Carl Djerassi’s first graduate students at Wayne State University, where he received his Ph.D. in Chemistry in 1958 for his work on the structure of coffee oil diterpenes and optical rotatory dispersion methods. From 1958–1967 Les worked at Lederle Laboratories as a natural product chemist, and rose to Group Leader of Antibiotic Discovery. He left Lederle for an appointment as Associate Professor of Natural Products Chemistry at The Ohio State University, where he was quickly promoted to Professor. In 1975, Les was recruited to Kansas as a University Distinguished Professor and Chair of Medicinal Chemistry. He remained Chair until 1992. Professor Mitscher has also held joint appointments at the University of Missouri-Kansas City and the Victorian College of Pharmacy (Melbourne, Australia). Over 50 students and postdocs were trained in the Mitscher lab, and Les has authored more than 280 research publications and 20 patents. He also authored or co-authored seven book on drug discovery, including several volumtes of the outstanding Organic Chemistry of Drug Synthesis series with Dan Lednicer. Les is the longest-serving consultant at Abbott Laboratories, and he consults extensively with several pharmaceutical companies and research organizations. He serves on the editorial board of numerous journals, and is a past Editor-in-Chief of Medicinal Research Reviews.

Always at the leading edge of drug discovery, the scope of Les’ work includes the discovery of clinically used antibiotics, key findings on the chemistry and mechanism of action of antibiotics and chemotherapeutic agents, herbal medicines, and the development of combinatorial chemistry methods. He is perhaps most well-known for his pioneering work on tetracyclines, quinolones, and erythromycin antibiotics.

As you might imagine, Les has been recognized with numerous honors and awards through his illustrious career, including: Smissman Award in Medicinal Chemistry (American Chemical Society), Volweiler Award (American Association for Pharmaceutical Education), Medicinal Chemistry Division Hall of Fame (American Chemical Society), Research Achievement Award in Natural Products Chemistry (American Pharmaceutical Association), Award in Medicinal Chemistry (American Chemical Society), Norman Farnsworth Research Achievement Award (American Society for Pharmacognosy), Fellow of the American Association for the Advancement of Science, and Emeritus Fellow of the International Union of Pure and Applied Chemistry.

This summary of Les’ accomplishments and impact on medicinal chemistry is not complete, and cannot do full justice to describing the lasting impact he has had. His current and former colleagues and group members can tell you many stories that provide insight as to what a wonderful, kind human being Les is.

You can probably gather the excitement I was feeling as my current graduate students (Mike Peterson, Will Fiers, and Yang Li) and I embarked on the seven-hour drive from Minneapolis to Lawrence. We had to wait for Will and Yang to finish their last final exam on Thursday morning, so we didn’t arrive to the Welcome Mixer at the Oread Hotel until about 8:00 pm after checking into our hotel and a quick change of clothes.

George Ellestad, Les Mitscher, and Dale Boger at the Welcome Mixer

Click on the picture to see more photos from the Mitscher Symposium.

The Oread is a beautiful, massive hotel located at the edge of the main campus, and the facilities there were top-notch. We ran into my dear friend Brian Blagg as we entered the lobby, and he helped point us to the back room where the reception was located. The room was filled with a celebratory air, and I quickly found Les and his lovely wife Betty to offer my congratulations. I was immediately struck by the outpouring of support for Les, as the room was filled with Kansas colleagues, symposium speakers, former group members, and KU alumni from other research groups. It was also great to catch up with alumni from my time at Kansas (1994–1999) such as Burchelle Blackman, Tim Caldwell, Suzanne Buck, and Jennifer Golden. Due to our late arrival, however, the reception ended too soon despite extending for nearly an extra hour. Since we didn’t have a chance to get dinner, my group and I left to catch at bite at Free State Brewery before calling it a night.

Les Mitscher and Dan Flynn at the Welcome Mixer

Click on the picture to see more photos from the Mitscher Symposium.

Coming in Part 2 of the LesFest recap: more pictures and a review of the symposium and banquet dinner, including my personal reflections on my time in his group.