Cover image for Vol. 12 Issue 18

Editorial Board Chairs: Karl-Heinz Altmann, Antonello Mai, Rainer Metternich. Editor: David Peralta

Impact Factor: 3.225

ISI Journal Citation Reports © Ranking: 2016: 17/60 (Chemistry Medicinal); 73/256 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics

February 13, 2013

11th Winter Conference on Medicinal and Bioorganic Chemistry, January 20–24, 2013, Steamboat Springs, Colorado (USA)

11th Winter Conference on Medicinal and Bioorganic Chemistry, January 20–24, 2013, Steamboat Springs, Colorado (USA)This year's WCMBC included about 40 presentations, most of which were given by researchers working in the private sector. The dozen or so talks from speakers in academic or government research settings brought fitting balance to the meeting nonetheless. As usual, the conference board managed to assemble an impressive lineup of presenters, granting delegates the privilege of seeing the latest developments in a wide range of medicinal chemistry sub-disciplines during the course of just over four days.

Since its beginning in the mid-1990s, the WCMBC series has provided biennial forums for sharing a high volume of top-notch research results and innovative ideas. Each meeting's setting is intimate, there are no parallel sessions, and the informal atmosphere is conducive to discussions and fruitful networking. The WCMBC events are unique in that they foster a healthy mixture of hard work and dedicated play. The traditional hockey match that pits Team R in blue against the rival white-clad Team S is a key event. Moreover, attendees can either hit the ski slopes or enjoy the blue Colorado skies in their own way during 5–6 hours of free time each afternoon. The popularity of this conference series is growing; attendance this year was about 150, up by roughly 30 from the 2011 meeting. As was the case two years ago, there were many new faces along with returning veteran delegates.


Innovations in Drug Candidate Development

The first session was chaired by Dr. Trevor Laird (Scientific Update, UK), who hosted talks on manufacturing routes, scale-up, and early process chemistry. Dr. Laird, founder of Scientific Update LLP (which organized the two latest WCMBC events), started the session by presenting some case studies of drug candidate development. He emphasized a number of potential thermal hazards in scale-up, including those in azide and hydride chemistry. This was followed with a talk by Dr. Carl Busacca (Boehringer–Ingelheim, USA) that detailed the development of a manufacturing route for faldaprevir, a hepatitis C (HCV) protease inhibitor. The route involves neither chromatography nor protecting groups, so is particularly amenable to large scale. Also on the topic of HCV, Dr. John Ragan (Pfizer, USA) discussed ways to control chirality at the multi-kilogram scale, exemplified by an enantioselective synthesis of the HCV RNA polymerase inhibitor filibuvir. Dr. Diane Carrera (Genetech, USA) wrapped up this session with a presentation on early process research, outlining a synthetic strategy for phosphoinositide 3-kinase δ inhibitors in which a palladium-catalyzed step is replaced by a metal-free reaction, and which also avoids the use of chromatography.

Cancer Cell Metabolism and Opportunities for Therapeutic Intervention

Monday morning began with a talk by Dr. Sandaruwan Geeganage (Eli Lilly & Co., USA), who discussed his team's work with inhibitors of NAD+ biosynthesis in their efforts to combat cancer by targeting the metabolic reprogramming that comes with oncogenesis. Prof. Richard Cerione (Cornell University, USA) gave an engaging presentation on
his group's discovery of glutaminase C as the target for a small molecule that was found to block fibroblast transformation, opening the potential to exploit the “glutamine addiction” exhibited by cancer cells. Dr. Matthew Boxer (NIH, USA) described how pyruvate kinase M2 (PKM2) has been linked to the effect of high lactate production by cancer cells regardless of oxygen levels (i.e., the Warburg effect); his group has shown that PKM2 activators can decrease tumor size in mouse xenograft models. Next, Dr. Janeta Popovici-Muller (Agios Pharmaceuticals, USA) presented her team's optimization of mutant isocitrate dehydrogenase 1 inhibitors identified by HTS for the treatment of cancer. The session concluded with two related presentations focused on blocking the same step in NAD+ biosynthesis as covered in the initial talk by Dr. Geeganage, namely that catalyzed by nicotinamide phosphoribosyltransferase (NAMPT): The first was by Dr. Ken Bair (Forma Therapeutics, USA), who discussed the structure-based identification of novel NAMPT inhibitors as part of a collaboration between Forma Therapeutics and Genentech. This was followed with a talk by Dr. Peter Dragovich (Genentech, USA) that covered the design of optimized NAMPT inhibitors.

Neglected Infectious Diseases and Parasitic Infections

Malaria and tuberculosis (TB) treatments were the focus of Monday afternoon's session. Dr. Bryan Yeung (Novartis, Singapore) started things off with his presentation on optimizing a spiroindolone antimalarial lead that was discovered by screening the Novartis natural product library. His team determined a novel mechanism of action for this compound class, and their optimized lead structure has entered phase 2 clinical trials. Dr. David Wilson (GlaxoSmithKline, UK) discussed how the current line of artemisinin-based combination therapies are under threat by emergent resistance; his group is therefore using phenotypic screens of the GSK Tres Cantos antimalarial set to derive novel antimalarial agents for lead optimization. Shifting attention to TB, Prof. Courtney Aldrich (University of Minnesota, USA) presented his group's work in the rational design and structural biology of nucleoside bisubstrate antibiotics that potently inhibit biotin protein ligase (BirA), an attractive new anti-TB target. Finally, Prof. Marvin Miller (University of Notre Dame, USA) gave an enlightening talk entitled Syntheses and Evaluation of New Anti-tuberculosis Agents Inspired by Studies of Mycobacterial Iron Assimilation, in which he discussed ways to exploit the selective uptake of sideromycin conjugates by bacteria as a route for the specific delivery of antibiotics.

Academic Session — Indiana University

Tuesday morning featured presentations by faculty at Indiana University. Prof. Nikki Pohl presented her research group's efforts in carbohydrate chemistry, highlighting some important challenges in glycan synthesis. Prof. Silas Cook outlined the need for an affordable route to fully synthetic artemisinin and then presented his group's successful progress in accessing this important antimalarial. Treatments for metabolic disease and obesity were addressed in Prof. Richard DiMarchi's talk, in which he described peptides that act as dual agonists toward receptors for endocrine hormones involved in glucose homeostasis. Prof. Erin Carlson described her research group's methods developed to facilitate the purification of natural products by chemoselective enrichment, expanding the general availability of biologically produced small molecules. Wrapping up the IU session, Prof. Charles Dann presented his structural biology research on human folate receptors and their potential for use in targeted drug delivery as a way to minimize the toxicity of antifolate drugs used in cancer and autoimmune disease chemotherapy.

Frontiers in Synthesis

Prof. Paul Chirik (Princeton University, USA) started the afternoon session with a talk about redox-active ligands and base metal catalysis for organic synthesis as an alternative approach to catalysis with expensive and toxic second- and third-row metals. Focus shifted to a more biological topic with the presentation by Dr. Scott Gilbertson (University of Houston, USA), who discussed a new approach toward 5-HT2C receptor (5-HT2CR) agonism for stimulant pharmacotherapy: blocking the protein–protein interactions in the complex between 5-HT2CR and PTEN, the latter of which suppresses 5-HT2CR activity. Dr. Paul Richardson (Pfizer Worldwide R&D, USA) gave a particularly entertaining talk entitled Facilitation of Scale-Up of Novel Oncology Candidates through Early Route Optimization — Risk and Rewards, in which he described how his team found ways to decrease the cost and complexity in the scale-up synthesis of two leads, both of which contain cyclopropane and bicyclo[1.1.1]pentane groups among various other synthetic challenges. Prof. Janis Louie (University of Utah, USA) concluded the day's talks with her presentation on the mechanistic details of nickel and iron-catalyzed cycloaddition reactions developed in her research group; these reactions are brief and take place under mild conditions.

New Frontiers in Medicinal Chemistry

Dr. Matt Hayward (Pfizer, USA) kicked off a day full of research insight from those in the pharmaceutical industry with his talk on the many advantages and risks of covalent inhibitors in drug design. Dr. Steve Colletti (Merck, USA) began his talk with some background on RNA interference, then covered recent advances in siRNA delivery following Merck's acquisition of Sirna Therapeutics. Dr. Antonia Stepan (Pfizer, USA) provided a nice follow-up presentation to Dr. Richardson's talk the previous day by discussing γ-secretase inhibitors bearing oxetane and bicyclo[1.1.1]pentane motifs; these unusual groups impart very attractive biopharmaceutical properties to this compound series. Dr. Colin Tice (Vitae Pharmaceuticals, USA)
discussed how his company's drug discovery and optimization program (Contour) is able to build computer-generated molecules with predicted potencies into known target active sites by linking drug-like fragments together through chemically sensible connections. He then showed examples of how this approach has enabled the discovery of a number of potent inhibitors. Dr. Serge Boulet (Eli Lilly & Company, USA) wrapped up the morning by discussing phenotypic drug discovery (PDD) as an alternative approach to the more conventional targeted drug delivery (TDD), in which shortcomings in molecular target validation can often play a role in late-stage clinical failures. He used angiogenesis as an example of a particularly suitable area for the use of PDD in place of TDD methods.

Open Session

Wednesday afternoon's open session started with a talk by Dr. Ed Olhava (Epizyme, USA) regarding his company's clinical candidate, EPZ-5676, for the treatment of MLL-rearranged leukemia. The compound is a histone H3 methyltransferase (DOT1L) inhibitor that resulted from optimizing initial hits from a structure-guided design approach. Dr. Jamie Tuttle (Pfizer, USA) presented his team's discovery of brain-penetrant kynurenine aminotransferase II (KATII) inhibitors for the treatment of schizophrenia. Their lead compound was found to form a covalent adduct with the PLP cofactor in the KATII active site; structural, biophysical, and computational studies are central to the group's characterization and drug design strategies. Dr. Rolf Wagner (Abbott, USA) concluded the session by detailing his group's discovery of the HCV polymerase inhibitors ABT-333 and ABT-072, both of which have completed phase 2b trials, with the former having been advanced to phase 3.

The subsequent poster session was energetic and inspiring, giving delegates a chance to stretch their legs a bit while taking in a wide range of research project summaries at their leisure. The ensuing conference dinner was followed by the Keynote Lecture, given by Dr. Peter Mueller (CSO & Executive VP, Global Research & Development, Vertex Pharmaceuticals, USA). His talk, entitled Imagine: Pharma Be Fractal, outlined the benefits of pharmaceutical companies changing from the conventional corporate hierarchy to a more horizontal, fractal-inspired reporting structure in order to meet the demands of increasing organizational complexity across the healthcare sphere, from basic science to the patient's bedside. For example, the science behind pharmaceutical R&D is far too advanced and complex for a small group of company executives to understand and manage sufficiently; therefore, companies with more distributed structures have an edge, as they can take much greater advantage of the collective expertise from a large number of scientists when it comes to making decisions that affect corporate direction. Dr. Mueller followed this up with the very inspiring success story of Vertex's Kalydeco, used in the treatment of cystic fibrosis.

Emerging Therapies for Hepatitis C

Thursday's session on HCV started with a talk by Dr. Omar Lopez (BMS, USA), who discussed his team's discovery of daclatasvir (BMS-790052), the first HCV NS5A replication complex inhibitor to show clinical proof of concept. Dr. Will Watkins (Gilead, USA) followed with his presentation on the advantages of direct-acting antiviral agents (DAAs) in HCV therapy and the optimization of HCV NS5B thumb site II inhibitors for use in interferon-free regimens. Dr. Andrew Woodhead (Astex, USA) then described how his group used fragment-based crystallographic screening to discover a novel allosteric binding site at the helicase–protease domain interface of the HCV NS3/4a protein. Binders of this allosteric site stabilize an inactive conformation of NS3/4a, providing a new way to treat HCV infections. The session concluded on the topic of covalent inhibition with a talk given by Dr. Deqiang Niu (Celgene, USA), who outlined how his team discovered a potent and selective irreversible HCV NS3 protease inhibitor that targets a non-catalytic cysteine residue in this protein.

Treatment of Lipid Disorders: Metabolic Syndrome and Beyond

The final session of this year's WCMBC was led by Dr. Jason Elliott (Novartis, USA), who started with some background on familial chylomicronemia syndrome (FCS). Due to an inability to break down fatty acids, FCS patients suffer very high plasma triglyceride levels and are therefore restricted to diets with extreme limitations on fat content. Given the key role of diacylglycerol acyltransferase 1 (DGAT1) in triacylglycerol biosynthesis, its inhibition leads to a decrease in circulating triglycerides. Dr. Elliott's group has identified a number of DGAT1 inhibitors that suppress postprandial triglyceride levels. Dr. Amjad Ali (Merck Research Laboratories, USA) then outlined the benefits of high-density lipoprotein (HDL-C) and its role in transporting cholesterol away from atherosclerotic plaques. The cholesteryl ester transport protein (CETP) decreases HDL-C levels, and so its inhibition is a way to ameliorate atherosclerosis. Dr. Ali discussed the discovery and clinical evaluation of anacetrapib, an orally active CETP inhibitor that has shown success thus far in a phase 3 clinical trial series. Dr. Jon Seiders (BMS, USA) presented his group's work on discovery and optimization efforts that led to AM095, an LPA receptor antagonist with efficacy in multiple mouse models of fibrosis. As the final presenter, Dr. Michael Vazquez (Pfizer, USA) discussed his research efforts to address osteoarthritic pain and inflammation while avoiding cyclooxygenase inhibition. His team developed a potent, selective, and orally bioavailable benzoxazole-based inhibitor of mPGES-1, which catalyzes the final step in prostaglandin E2 biosynthesis, and its efficacy was demonstrated in a number of animal model studies.

Hockey Tradition

The hockey game on Tuesday night had all spectators — a small but loud group of elite enthusiasts — on the edge of their seats. It was a close game into second period, with the score tied at 2–2. However, Team S began to pull away with a 3–2 lead roughly halfway through the game, and all throughout the third and final period they never looked back, securing their firm hold on the WCMBC Cup for another two years with a 5–2 victory. It wasn't easy, as Team R had an impressive number of shots on goal, but the (S)-goalie denied each one. This is the second victory in a row for Team S after a long run of wins for Team R, who will need to develop a firm strategy for the 2015 game.


The Medicinal and Bioorganic Chemistry Foundation (MBCF) Board and conference organizers put together a superb meeting once again. Despite the added challenge of significant flight delays and lost luggage for some organizers this year, they came through with flying colors. The 12th WCMBC will be held January 25–29, 2015. More information about this conference series can be found at the MBCF website:

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