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WEDNESDAY, MAY 21, 2014

  

THE FUTURE ROLE OF MEDICINAL CHEMISTRY – AN EXECUTIVE PERSPECTIVE 

7:00 am Registration and Morning Coffee

8:00 Chairperson’s Opening Remarks

Eddine Saiah, Ph.D., Atlas Venture

8:05 The Future Role of Small Molecule Research

Hans-Joachim Boehm, Ph.D., Global Head, Small Molecule Research, Roche

Medicinal chemistry has delivered many outstanding therapies that have revolutionized the treatment of serious diseases. Nevertheless, there remain challenges, such as tackling protein-protein interactions, targeting certain cell types or organs and developing new strategies to avoid off-target toxicity. I will present work from Roche trying to address these issues and will provide an outlook about the future of small molecule research.

8:35 Medicinal Chemistry v2.0

Mark Bunnage, D.Phil., Vice President, Head, Chemistry, Biotherapeutics Research, Pfizer, Inc.

Pharmaceutical R&D has been undergoing significant change in recent years in response to its productivity challenges. This presentation will discuss the role of medicinal chemistry in this evolving R&D ecosystem and highlight new areas of opportunity for medicinal chemists to enable future drug discovery.

9:05 Strategic, Organizational and Cultural Considerations for Medicinal Chemistry Practices

Mike Hann, Ph.D., Director, Chemical Sciences, R&D Platform

Technology & Sciences, GlaxoSmithKline

While medicinal chemistry is one of the core disciplines that contribute to drug discovery, it is a complex and evolving subject which is sometimes seen as the cause rather than the solution to the problems we face in the pharma industry of low return on investment. This presentation will take a look at some of issues that have influenced this debate (e.g. libraries, HTS, informatics, time pressure and resource, outsourcing, specialists vs. generalist, etc) and discuss how we can ensure medicinal chemistry remains at the core of drug discovery and alive to the opportunity that high attrition continues to challenge us with.

9:35 Coffee Break in the Exhibit Hall with Poster Viewing

10:20 Driving Medicinal Chemistry through Collaborative Networks

Joerg Holenz, Ph.D., Director, Discovery & Preclinical Sciences, AstraZeneca Pharmaceuticals

Neuroscience is a complex area with high unmet medical need where many biopharmaceutical companies have scaled back. In 2012, AstraZeneca pioneered a novel externally facing approach of driving R&D projects via collaborative networks with academic and industry partners. This talk will introduce this approach and focus on how medicinal chemistry is flexibly organized within our model to successfully drive the Design-Make-Test cycle within preclinical projects.

10:40 PANEL DISCUSSION: The Future Role of Medicinal Chemistry

Moderator: Michael Block, Ph.D., former Executive Director, Chemistry, AstraZeneca Boston

Panelists:

Hans-Joachim Boehm, Ph.D., Global Head, Small Molecule Research, Roche

Mark Bunnage, D.Phil., Vice President, Head, Chemistry, Biotherapeutics Research, Pfizer, Inc.

Mike Hann, Ph.D., Director, Chemical Sciences, R&D Platform Technology
& Sciences, GlaxoSmithKline

Joerg Holenz, Ph.D., Director, Discovery & Preclinical Sciences, AstraZeneca Pharmaceuticals

• New organizational models driving medicinal chemistry virtual models, outsourcing, collaborative tools, partnerships
• Re-focus on receptor kinetics, difficult targets with peptides, allosteric and covalent inhibition, tissue targeting by design, neglected diseases and natural products

CASE STUDY SESSION: PART I 

11:00 Chairperson’s Remarks

Ivan Kondratov, Ph.D., Head, Medicinal Chemistry, Enamine

11:05 Marketed and Clinical Macrocycles – Food for Thought

Fabrizio Giordanetto, Ph.D., Director, Medicinal Chemistry, Taros Chemicals GmbH & Co. KG

Macrocycles have gained renewed popularity for drug discovery applications in recent years due to perceived advantages in terms of affinity, selectivity, metabolic stability and especially oral absorption. An analysis of currently marketed macrocycles and macrocycles in clinical development is presented to investigate such advantage claims.

 

11:25 The Discovery and Profile of Narrow Spectrum Kinase Inhibitors as Novel Treatments for Inflammatory Pulmonary Diseases 

Stuart Onions, Ph.D., Director, Research Management, Sygnature Discovery Ltd

COPD affects 65 million people worldwide and by 2030 could be the third largest cause of death. Corticosteroids remain the front line intervention, but a widespread insensitivity and inability to effect disease progression with these agents is driving the need for new, improved therapies. This presentation details the discovery of narrow spectrum kinase inhibitors which maximize the beneficial effect on the target organ, promote optimal duration of action and reduce the potential for toxicity by minimizing systemic exposure.

11:55 Novel Inhibitors of 11ß-Hydroxysteroid Dehydrogenase Type 1

Kurt Ritter, Ph.D., Senior Scientist, Sanofi

Selective inhibition of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) offers the potential as a novel treatment for type 2 diabetes and obesity by controllingintracellular cortisol levels. Our lead series resulted from an impurity found in a hit sample of a high throughput screening campaign on 11ß-HSD1. The talk will cover the elucidation of the structure of the highly active impurity, its binding mode to the enzyme and the optimization of the series.

12:25 pm Covalent Inhibition in Medicinal Chemistry Drug Design: Reversible Covalent Inhibitors of Bruton’s Tyrosine Kinase for Autoimmune Diseases

Suvit Thaisrivongs, Ph.D., Head, Immunoscience Research Unit Chemistry, Worldwide Medicinal Chemistry, Pfizer, Inc.

One drug design strategy for achieving pharmacological potency and selectivity for kinase targets is to engage the non-catalytic cysteine residues with covalent inhibitors. The utilization of covalent inhibitors that reversibly form adducts provides the pharmacodynamic benefit with reduced liability of long-lived irreversible protein adducts. Structure-based design led to the discovery of such a class of inhibitors for BTK. The optimized compound has been shown to be efficacious in several pre-clinical animal models of arthritis and autoimmune diseases.

 

12:55 Luncheon Presentation: Applications of Structure-Based Computation to Drive Lead Optimization

Woody Sherman, Ph.D., Vice President, Applications Science, Schrödinger, Inc.

Computational tools for structure-based drug design have been used in pharma for decades, but their successful application has been limited due to a variety of challenges. Here, we focus on three important issues that have challenged the field: proper force field treatment of small molecules, accurately accounting for solvent thermodynamics, and sufficient conformational sampling. We show that more rigorous treatment of these issues can produce a qualitative improvement in the predictive capabilities of computational tools. We describe several key advances made in recent years and show examples where the tools have demonstrated value in lead optimization campaigns.

1:30 Session Break

CASE STUDY SESSION: PART II 

2:00 Chairperson’s Remarks

Stewart L. Fisher, Ph.D., Principal, SL Fisher Consulting, LLC

2:05 Inhalation by Design – p38 Inhibitors for COPD

John Mathias, Ph.D., Senior Director & Head, Medicinal Chemistry, Inflammation & Remodeling, Pfizer, Inc.

This talk details the medicinal chemistry design of our PII inhaled p38 inhibitors in 3 key areas: 1. Engineering in slow onset/offset kinetics and some kinetic-structure relationships we derived to maximize lung efficacy following inhalation, 2. Lung targeting to ensure physical residence in target organ, 3. Designing to drive low systemic bioavailability and low potential active metabolite burden following inhalation.

TISSUE TARGETING BY DESIGN:
FROM ADCs TO NANOPARTICLES 

2:35 Medicinal Chemistry Approaches to the Design of Novel Linkers, Payloads and Antibody-Drug Conjugates for the Treatment of Cancer

Chakrapani Subramanyam, Associate Research Fellow, World Wide Medicinal Chemistry, Pfizer

Antibody drug conjugates (ADCs) are an established modality for the treatment of cancer. This talk will focus on Pfizer’s chemistry strategy to discover and develop new linker-payload classes and conjugation methods that yield more efficacious and potentially better tolerated ADC that are being advanced to the clinic.

3:05 Novel Linker-Duocarmycin Payloads for Next-Generation Antibody-Drug Conjugates

Patrick Beusker, Ph.D., Director, Antibody-Drug Conjugates, Synthon

ADCs are emerging as a new modality for cancer treatment. Despite the impressive results obtained thus far, there is still need for improvement. Our novel linker-duocarmycin payloads have been designed to provide ADCs with excellent efficacy and a high therapeutic index. Design and application of this linker-drug technology will be discussed.

 

3:35 Incorporating Macrocyclic Expertise into Protein-Protein Interaction Ligand Design 

Roman Kombarov, Ph.D., Project Manager, ASINEX

Protein-Protein interactions have great potential as therapeutic targets but are currently one of the most challenging areas in drug discovery. At Asinex, we have developed a platform that uses macrocyclic elements to facilitate the efficient design of novel alpha-helix mimetics which are decorated with poly-substituted hydrophobic substituents. These structures have the correct geometry and substitution characteristics to align the requisite functional groups in three dimensions and are thus able to disrupt key elements of the PPI interface. This talk will focus on how this strategy addresses an unmet need in drug discovery.

3:50 Targeting Specific Interactions to Improve Binding Properties of EGFR-Kinase Ligands

Chris Williams, Ph.D., Principal Scientist, Chemical Computing Group

Structure-based drug design, combined with PDB data-mining, protein structural fingerprints and pharmacophore searches was used to help identify and characterize linkers for connecting EGFR-binding moieties to DNA and Src targeting functionalities. The resulting compounds showed EGFR inhibitory potency in the low micromolar to nM range and retained significant activity against their divergent targets.

 4:20 Refreshment Break in the Exhibit Hall with Poster Viewing 

TOUGH TARGETS: ALLOSTERIC INHIBITORS
TO ENHANCE PROFILES OR MODULATE DIFFICULT TARGETS 

5:00 Allosteric Modulation of Phospholipase D: Oncology, Virology and Beyond

Craig W. Lindsley, Ph.D., Director, Medicinal Chemistry, Vanderbilt University Medical Center

This talk will describe the chemical optimization of allosteric, isoform selective PLD inhibitors and the challenges therein. With highly selective tools, it was now possible to dissect the physiological roles of PLD1 and PLD2. Data presented will make a compelling case for PLD inhibition as a novel mechanism for therapeutic intervention across a broad spectrum of diseases.

5:30 Molecular Mechanism of SSR128129E, an Extracellularly Acting Small Molecule Allosteric Inhibitor of FGF Receptor Signaling

Chantal Alcouffe, Medicinal Chemistry Team Leader, Early to Candidate, Sanofi

Protein-protein interactions (PPI) mediate many important biological processes and represent an emerging and challenging area in drug identification. Allosteric modulators offer a competitive advantage, as specificity or safety, over orthosteric antagonists. Receptors for fibroblast growth factors belong to RTK family. FGF receptor (FGFR) signaling has been widely implicated in many pathologies such as cancer. They contribute to the tumor progression by promoting tumor cells proliferation, migration, invasion and also by stimulating angiogenesis. They also participate to intrinsic and acquired resistances to current anti-cancer therapies. In this context, the SSR128129, a FGFR inhibitor, which binds to the extracellular domain of the receptor, has been identified. Cellular assays, signal transduction analysis, crystallization, Fourier transform infrared spectroscopy, mutagenesis, molecular dynamics simulations and metadynamics free energy calculations experiments participate to the elucidation of the allosteric mode of action of SSR128129. Then, this mechanism of action has been validated with structure activity relationship analysis based on signaling assays, NMR and molecular dynamics experiments. At last, SSR128129 is the first reported small molecule allosteric inhibitor of FGF/FGFR signaling, acting via binding to the extracellular part of the FGFR.

6:00 Welcome Reception in the Exhibit Hall with Poster Viewing

7:00 End of Day

 

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