2017 Archived Content
The Drug Discovery Chemistry conference will bring together drug discovery scientists from pharma/biotech companies and academia to talk about new technologies, open innovation, collaboration, and insightful case studies. It will cover topics that are
very important and relevant to medicinal chemists that include hit-to-lead identification and validation, lead optimization, designing safer drugs, working with new targets and drug modalities, evaluating new technologies for drug synthesis and screening
and more.
Recommended Package:
Final Agenda
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Thursday 16 November
12:00 Registration
13:30 Chairperson’s Opening Remarks
Neil Press, Ph.D., FRSC, Director, Global Discovery Chemistry, Novartis
13:35 Inhaled Drug Delivery Challenges – Development of a Long-Acting M3 Receptor Antagonist
Neil Press, Ph.D., FRSC, Director, Global Discovery Chemistry, Novartis
Systemic side effects associated with drugs may be reduced through topical delivery, e.g. to the lungs. Our approach to the special challenges of developing inhaled drugs, such as formulation, formulatability, duration of action, clearance and tolerability,
will be exemplified by the design of new M3 receptor antagonists for COPD, culminating in the development of a clinical candidate with excellent efficacy and long duration of action.
14:05 Discovery of AMPA Receptor Modulators Selective for TARP γ-8
Mike Ameriks, Ph.D., Senior Principal Scientist, Neuroscience Chemistry, Janssen R&D
Glutamate mediates fast synaptic transmission in the brain via activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPAR activity can be modulated by transmembrane regulatory proteins (TARPs), which are often localized
in distinct brain regions. Herein, we describe AMPAR negative modulators selective for TARP-γ8, the primary TARP in hippocampus, and demonstrate that these compounds exhibit anticonvulsant activity in rodents without the motor impairment associated
with conventional anti-epileptics.
14:35 Supporting Compound Optimisation in Not-For-Profit and Academic Research
Nick Foster, Head of Commercial Operations, Optibrium Ltd.
The not-for-profit
and academic sectors have become important sources of novel drug candidates,
particularly for neglected and developing world diseases or niche indications.
Discovering new drugs in these sectors is even more challenging than in pharma for
a number of reasons: challenging diseases, often affecting the developing word
and with emerging resistance to current therapies; limited resources; and the
need to manage complex data, often generated across large multi-centre
collaborations. In this context, the need to make good decisions regarding
which compounds to synthesise and assays to perform is critical. We will
describe an anti-malarial project and how integrated cheminformatics and
computational chemistry software helped to guide the design of new compounds
with a better chance of downstream success.
15:05 Refreshment Break in the Exhibit Hall with Poster Viewing
15:45 SMN2 Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)
Hasane Ratni, Ph.D., Senior Principal Scientist, Roche Pharmaceutical Research and Early Development,
Roche Innovation Center Basel, F. Hoffmann-La Roche
Spinal muscular atrophy (SMA) is the leading genetic cause of infant and toddler mortality. Herein, we report the identification of an orally available series of small molecules that modify the alternative splicing of SMN2 gene, restoring the levels of
full-length SMN protein in two mouse models of SMA. Lead optimization culminated in the discovery of RG7800, the first small molecule SMN2 splicing modifier to enter human clinical trials, and of RG7916, currently in clinical trial in patients.
16:15 Creation of a Novel Class of Potent and Selective MTH1 Inhibitors Using Fragment-Based Design
Jenny Viklund, Ph.D., Principal Scientist, Computational Chemistry, Sprint Bioscience
Tumor cells are highly dependent on mechanisms to deal with reactive oxygen species (ROS) stress. Enzymes involved in sanitization of the nucleotide pool have been shown to be important for tumor cell survival. MTH1 is an enzyme involved in degradation
of oxidized dGTP to prevent its incorporation into DNA and has been hypothesized to be an attractive target for anti-cancer drug discovery. This presentation describes our fragment-based approach to create potent and selective inhibitors of MTH1
with promising drug-like properties and their use to evaluate the effects of pharmacological inhibition of MTH1 on tumor cell survival.
16:45 Development of an X-Ray Fragment Hit into Inverse Agonists of the Nuclear Hormone Receptor RORc
Ulf Börjesson, Ph.D., Senior Research Scientist, Hit Discovery, Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca
Here we describe the discovery of inverse agonists of the retinoic-related orphan receptor gamma (RORc), using a fragment hit identified in a primary X-ray screen as a starting point for structure-based design. This lead series has an attractive
solubility profile and represents a rare case of progression of a fragment hit identified by biophysical methods into functional modulators of a nuclear hormone receptor.
17:15 Breakout Discussion Groups
This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas
and active networking.
TOPIC: The Importance of Target Identification and Validation in Drug Discovery
Moderators:
Neil Press, Ph.D., FRSC, Director, Global Discovery Chemistry, Novartis
Guy Breitenbucher, Ph.D., Senior Director, Discovery Chemistry, Dart NeuroScience
- Initial target identification and validation techniques
- Assay development and high throughput screening
- Lead optimization and selecting clinical candidate
TOPIC: Use of Chemical Biology and Chemical Probes in Drug Discovery
Moderators:
José Ignacio Andrés, Ph.D., Scientific Director & Fellow, Discovery Sciences, Lead Discovery Chemistry, Janssen Researc
h & Development
Paul Brennan, Ph.D., Associate Professor, Medicinal Chemistry, University of Oxford and Principal Investigator, Target Discovery Institute, Structural Genomics Consortium
- Main applications of Chemical Biology in Drug Discovery projects
- When should Chemical Biology be used in Discovery programs?
- Labelled and label-free proteomic techniques for target identification
18:00 Dinner Short Course Registration
18:15 Close of Day
18:30 Recommended Dinner Short Course*
(SC5) The Role of Drug Transporters in Drug Research and Development
*Separate registration required,
Day 1 | Day 2 | Speaker Biographies | Download Brochure
Friday 17 November
8:00 Registration and Morning Coffee
8:25 Chairperson’s Remarks
Malin Lemurell, Ph.D., Head of Medicinal Chemistry, Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca
8:30 Isoform Selective, Novel PKI CNS Drug Candidate through Integrated Use of Pharmacoinformatics and Structural Genomics
D. Martin Watterson, Ph.D., John G. Searle Professor of
Molecular Biology and Biochemistry, Northwestern University and Professor of
Pharmacology, Feinberg School of Medicine
Delivery of protein kinase (PK) inhibitor drug candidates for neurodegenerative diseases, neuropsychiatric disorders and neuro-oncology face two major challenges: blood brain barrier penetrance and PK selectivity with active site targeting, the prevailing approach for approved PKI drugs. A case study from a platform using pharmacoinformatics integrated with recursive structure assisted design will be discussed as a candidate deliverable.
9:00 Dissecting Non-Additive SAR
Guy Breitenbucher, Ph.D., Senior Director, Discovery Chemistry, Dart NeuroScience
The determination of Free-Wilson Additivity within a combinatorial matrix of compounds has significant implications for how future SAR is conducted. I will present a number of case studies from real medicinal chemistry programs where the
use of quantitative additivity determinations had significant impact on the progression of the program. Including a recent unpublished example using PDE2 inhibitors, where for the first time, non-additive SAR could prospectively predict
a change in ligand binding mode within the protein crystal structure.
9:30 New Modalities for Treatment of Cardiovascular and Metabolic Diseases
Malin Lemurell, Ph.D., Head of Medicinal Chemistry, Cardiovascular and
Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca
Today we see immense data being generated from patient material providing a range of exciting novel biological pathways and targets linked to disease. Several of these provide a challenge from a druggability perspective. The strategy we have embarked on to embed new modalities in our capabilities, and some recent examples of how we used new modalities to find ways of modulating challenging targets or to widen therapeutic window through tissue targeting, will be presented.
10:00 Urea-Based Prostate Specific Membrane Antigen (PSMA) Ligands for the Diagnosis and Therapy of Prostate Cancer
Alan P. Kozikowski, Ph.D., CEO and President, StarWise Therapeutics
LLC
Prostate cancer cells overexpress prostate-specific membrane antigen (PSMA) relative to untransformed prostate cells. The popular urea scaffold first created by our research group has been employed by many to target and inhibit PSMA
in the nM range. Recently, we have developed a new series of urea-based PSMA ligands that show sub-nM potencies. The chemistry, modeling, and X-ray studies of this newer scaffold and possible extension to a host of diagnostic and
therapeutic interventions will be detailed.
10:30 Coffee Break in the Exhibit Hall with Poster Viewing
11:15 Chemical Probes – Applications and Impact across Drug Discovery Research
Werngard Czechtizky, Medicinal Chemistry, Respiratory,
Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
Chemical probes play an increasingly important role in drug discovery due to e.g. the demand for earlier target validation, improved assay development for meaningful decision trees, and proof of mechanism of action and target engagement.
This presentation includes an overview on different types and applications of chemical probes for chemical biology purposes.
11:45 Fragments to Chemical Probes for Epigenetic Targets
Paul Brennan, Ph.D., Associate Professor, Medicinal Chemistry, University
of Oxford and Principal Investigator, Target Discovery Institute, Structural Genomics Consortium
Epigenetic effects due to persistent changes in gene transcription have been linked to chemical modification of DNA and histone proteins that package and regulate DNA in the nucleus. There are hundreds of potential drugs targets associated
with histone modifications. By using crystallographic screening of poised fragments and rapid analogue synthesis, we are developing chemical probes for uncharacterized bromodomains, the principle readers of histone acetylation.
12:15 Discovery and Application of New PET Ligands: A Robust Medicinal Chemistry Strategy Is Required to Ensure Success
José Ignacio Andrés, Ph.D., Scientific
Director & Fellow, Discovery Sciences, Lead Discovery Chemistry, Janssen Research & Development
Positron emission tomography (PET) is a powerful diagnostic tool, increasingly used in drug discovery and development to demonstrate target engagement and monitor disease progression, particularly in neuroscience. Success in discovering
new PET tracers to support drug development relies on a robust medicinal chemistry strategy. Our team at Janssen R&D has discovered several new promising PET ligands following different medicinal chemistry approaches that
will be discussed herein, focusing on mGluR2 NAM and Tau PET ligands.
12:45 Enjoy Lunch on Your Own
13:15 Session Break
14:15 Chairperson’s Remarks
Eric Marsault, Ph.D., Professor, Department of Pharmacology-Physiology, Université de Sherbrooke
14:20 Unraveling Pharmacology of Anti-Cancer Natural Products
Tiago Rodrigues, Ph.D., Senior Post-doctoral Scientist, Department of Chemistry, Instituto de Medicina Molecular; Universidade de Lisboa
This talk will discuss methods for harnessing the power of natural product architectures in cancer chemical biology. By identifying on- and off-targets for anti-cancer entities and unveiling the underlying molecular mechanisms
of target recognition, we explore the use of natural products as cancer modulators and ligands for the selective delivery of cytotoxic payloads.
14:50 Optimizing the Permeability of Semi-Peptidic Macrocycles, One Atom at a Time
Eric Marsault, Ph.D., Professor, Department of Pharmacology-Physiology,
Université de Sherbrooke
Macrocycles generate a high level of interest for their unique potential ability to combine large surface areas and suitable drug-like properties. While macrocyclic peptides have been extensively analyzed to define islands of permeability,
studies of semi-peptidic macrocycles, which constitute a rapidly increasing sub-class among clinical candidates, are scarce. We will discuss recent data on the structure-permeability relationship of macrocycles composed of
a tripeptide cyclized head-to-tail with a non-peptidic linker.
15:20 Discovery of Potent Cyclophilin Inhibitors Based on Structural Simplification of Sanglifehrin A
Vicky Steadman, Ph.D., Director of Drug Discovery, Cypralis
Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this presentation, a set of synthetic
macrocyclic cyclophilin inhibitors inspired by the core structure of the natural product sanglifehrin A will be discussed. Sanglifehrin A has a molecular weight of over 1000 and 17 stereocenters. In contrast, our simplified
macrocycles, accessible via chemical synthesis, have molecular weights of around 500, only 4 stereocentres and yet achieve similar levels of inhibitory potency against cyclophilin and superior pan-genotype anti-viral activities.
15:50 Close of Conference
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