Emergence of irreversible modulation in drug discovery




Irreversible covalent modulation is a crucial part of the drug discovery toolbox and is an important strategy for finding tractable equity against less druggable targets. However, understanding the binding kinetics, mechanistic PK/PD relationship and SAR of compounds is critical to success as is employing best practice in hit identification and lead optimisation.

Join us in Cambridge on 16-17 October 2024, where we will bring together established leaders and emerging investigators exploring the use of irreversible covalent modulators in drug discovery. Targeting of both cysteine and other amino acid residues will be considered as will in depth analysis of the kinetics of irreversible inhibition. Irreversible modulation as a strategy for targeted protein degradation and the identification of covalent chemical equity through proteomic approaches will also be covered.

Learning outcomes:
Our expectation is that the meeting may serve to:

1). Build a network amongst research interested in irreversible modulation in drug discovery
2). Establish the framework for understanding kinetics in drug discovery for irreversible binders
3). Enable researchers to better understand and optimise chemical tools, leads and drug candidates

Session recordings will also be made available to registrants.

Save with our early bird discount! Ends 2 August 2024.

 

                             Day 1: In vitro approaches to irreversible modulation

09:00 – 10.15    Registration and coffee
 
10.15 – 10:30 Welcome and introduction
Steve Rees, 
Senior Vice President, AstraZeneca 
Bharath Srinivasan, Principal Scientist, AstraZeneca 

 
                                                                             Session one
10:30 – 11.00 David Mann, Imperial College London
"Identifying and developing covalent fragment hits for targeted therapeutics"
             
11.00 – 11.15 Oral Presentation 1
 
11:15 – 11.45 Monique Mulder, Leiden University Medical Center 

"Unveiling the Ubiquitin System through Covalent Enzyme Inhibition"

11.45 – 12.05

Fidabio - Partner session
Speaker: Henrik Jensen, CSO
"In-solution binding kinetics with 1st principle technology FIDA"

12.05 - 13:30 Lunch & Poster session
 
                                                                              Session two
13:30 –14:00 Nir London, Weizman Institute of Science
“New functions for covalent binders”
               
14:00 –14:15 Oral Presentation 2
 
14:15 – 14:45 Andrea Gohlke, AstraZeneca
“Electrophile first lead generation for an intractable target”
 
14.45 – 15.05  Enzymlogic - Partner session 
Speaker: TBC 

 
15.05 - 15:30 Coffee break
 
                                                              Session 3: Beyond cysteine
15:30 – 16:00 Emma Grant, GlaxoSmithKline
“Reactive fragment platforms for covalent hit ID”
 
16:00 – 16:15 Oral Presentation 4
 
16.15 -  16.45  Lyn Jones, Dana-Farber Cancer Institute
"Covalent Drug Development - Targeting Cysteine and Beyond"
 
16:45 – 17:00  Closing remarks
 

 
                                        Day 2: Cellular approaches to irreversible inhibition
 
09:45 – 10:15 Registration and coffee
 
10:15 - 10:30 Welcome and introduction
 
                                                                            Session one
10:30 –11:00 Megan Matthews, University of Pennsylvania 
"The revolution and evolution of activity-based protein profiling"
 
11:00 – 11:30 Speaker: TBC
 
11:30– 11:45 Oral Presentation 6
 
11:45 – 12:05  OmicScouts - Partner session
Speaker: TBC

 
12:05 - 13:15 Lunch & Poster session
 
                                                                               Session two
13:15 – 13:45    Matt Patricelli, Vividian Therapeutics
"Lessons and learnings from 8 years of chemoproteomics-centered drug discovery"
                                          
13:45 – 14:15 Speaker: TBC
 
14:15 – 14:30 Oral Presentation 7
 
14:30 – 14:50 Partner session (TBC) 
 
14:50 - 15:30 Break & refreshments
 
                                                                               Session three
15:30 – 16:00 Brent Martin, Scorpion therapeutics
“Streamlined live cell covalent ligand discovery”
 
16:00 – 16:30 Daniel K. Nomura, University of California, Berkley
“Reimagining Druggability using Chemoproteomic Platforms”
 
16:30 – 16:45 Oral Presentation 8
 
16:45 – 17:15 Concluding remarks & Awards
 
                                                                            Conference close

Professor Daniel Nomura 



Speaker: Professor Daniel Nomura, The University of California, Berkeley

Talk title: Reimagining Druggability using Chemoproteomic Platforms 

Biography: Dan Nomura is a Professor of Chemical Biology and Molecular Therapeutics in the Department of Chemistry and the Department of Molecular and Cell Biology in the Division of Molecular Therapeutics at the University of California, Berkeley and an Investigator at the Innovative Genomics Institute. He is an Adjunct Professor in the Department of Pharmaceutical Chemistry at UCSF. Since 2017, he has been the Director of the Novartis-Berkeley Translational Chemical Biology Institute focused on using chemoproteomic platforms to tackle the undruggable proteome. He is Co-Founder of Frontier Medicines, a start-up company focused on using chemoproteomics and machine learning approaches to tackle the undruggable proteome. He is also the Founder of Vicinitas Therapeutics based on his group’s discovery of the Deubiquitinase Targeting Chimera (DUBTAC) platform for targeted protein stabilization. He is on the Scientific Advisory Boards for Frontier Medicines, Vicinitas Therapeutics, Photys Therapeutics, Apertor Pharma, Ecto Therapeutics, and Oerth Bio. Nomura is also on the scientific advisory boards of The Mark Foundation for Cancer Research and the MD Anderson Cancer Center. He is also an Investment Advisory Partner at a16z Bio+Health, an Investment Advisory Board member at Droia Ventures, and an iPartner with The Column Group. He earned his B.A. in Molecular and Cell Biology in 2003 and Ph.D. in Molecular Toxicology in 2008 at UC Berkeley with Professor John Casida and was a postdoctoral fellow at Scripps Research with Professor Benjamin F. Cravatt before returning to Berkeley as a faculty member in 2011. Among his honors include the National Cancer Institute Outstanding Investigator Award, Searle Scholar, and the Mark Foundation for Cancer Research ASPIRE award.

Professor Nir London



Speaker: Professor Nir London, Weizmann Institute of Science, Rehovot, Israel

Talk title: New functions for covalent binders

Biography: Prof. Nir London completed his PhD in computational structural biology at the Hebrew University in 2012. He then pursued a post-doctoral fellowship with Brian Shoichet at UCSF. In 2015 Dr. London joined the Weizmann Institute of Science. Dr. London’s lab is focused on covalent chemical biology and is developing new technologies to discover and functionalize covalently acting compounds. His honors include amongst others, the 2021 EFMC award for young medicinal chemist in academia and the 2021 ISCB award for young chemical biologist. He is currently the president of the Medicinal Chemistry Section of the Israel Chemical Society.

Emma Grant 



Speaker: Emma Grant, GlaxoSmithKline

Talk title: Reactive fragment platforms for covalent hit ID

Biography: Emma conducted her PhD studies on the collaborative programme between the University of Strathclyde and GlaxoSmithKline. Her research primarily focussed on photoaffinity labelling and the development of a reactive fragment screening platform, known as the PhABits, to identify tool compounds for target validation. Since graduating in 2020 and being awarded the SCI Young Chemist in Industry Prize, Emma’s work has focussed on the expansion of reactive fragment screening platforms for covalent drug discovery. She now leads the application of these technologies in covalent hit ID and to assess target tractability in the Chemical Biology group within GSK. She was recently awarded a 2023 TechWomen100 prize for her research.

Brent Martin


 

Speaker: Brent Martin, Scorpion Therapeutics

Talk title: Streamlined live cell covalent ligand discovery 

Biography: Brent Martin received his Ph.D. in Pharmacology at the University of California in San Diego followed by postdoctoral studies at the Scripps Research Institute. As faculty member in the Chemistry Department at the University of Michigan in Ann Arbor, his research expanded the scope of activity-based profiling methods, developed new bioconjugation reactions to identify redox modifications and lipid modifications, and introduced tunable electrophiles for cysteine profiling. Brent left academics to lead the Chemical Biology team at Janssen. He is currently Vice President and Head of Chemical Biology at Scorpion Therapeutics.

Dr Andrea Gohlke


 

Speaker: Dr Andrea Gohlke, AstraZeneca PLC, Cambridge, UK

Talk title: Electrophile first lead generation for an intractable target

Biography: Dr. Andrea Gohlke is an Associate Director in Biophysics leading a team within the Mechanistic and Structural Biology department at AstraZeneca in Cambridge, UK. She joined AstraZeneca in 2019 and is using Biophysics in early- stage cancer drug discovery providing essential information about binding kinetics and the mode of action. In addition, she is a project leader including new capability developments. Starting her scientific career, she studied Molecular Life Science and obtained her PhD in Biophysical Chemistry at TU Dortmund in Germany in conjunction with the Max Planck Institute for Molecular Physiology in 2010. Here, she biophysically characterised the interaction of amyloids and small GTPases with model membranes and cells and how these can be modified. After that, she worked as postdoc in the group of Nobel laureate James Rothman at Yale University (USA) as well as at the École Normale Supérieure (France) studying SNARE-mediated membrane fusion using model membranes. Her work has been acknowledged with a postdoctoral fellowship from the German Research foundation. In 2015 she joined the Drug Discovery Programme at the CRUK Beatson institute (UK) where she used Biophysics in early-stage cancer drug discovery as well as lead collaborations with academic institutions. Her general scientific focus is the biophysical characterisation of protein/ligand interactions using a range of spectroscopic and microscopic methods. She is also a member of the publication committee of the Biophysical Journal. 

Dr David Mann 



Speaker: Dr David Mann, Imperial College London, UK

Talk title: Identifying and developing covalent fragment hits for targeted therapeutics

Biography: PhD Sheffield on developmental gene expression
Post doc in the MRC Protein Phosphorylation Unit headed by Prof Sir Philip Cohen in Dundee
Postdoctoral fellow at Imperial Cancer Research Fund (became London Research Institute of CRUK) on cell cycle dependent phosphorylation with Prof Nic Jones
Research Lecturer at Brunel Univeristy
Current post at Imperial College (started 2000) focussing on molecular/chemical biology of cancer

Matt Patricelli



Speaker: Matt Patricelli, Vividion Therapeutics, USA

Talk title: Lessons and learnings from 8 years of chemoproteomics-centered drug discovery

Biography: Obtained PhD from The Scripps Research Institute under Prof. Benjamin Cravatt (was his first student). More than 20 years of experience in the fields of enzymology, chemical biology, chemical proteomics, and drug discovery. Developed cutting edge chemical proteomics methodologies that formed the foundation of the ActivX activity-based proteomics platforms used for both internal drug development and a successful fee-for-service business (KiNativ). Biology lead for the KRAS-G12C program at Wellspring biosciences leading to the first demonstration of selective KRAS-G12C inhibition in cells and in vivo. 1st Employee and founding scientist of Vividion therapeutics. Built initial team, established chemoproteomics screening platform and early results leading to Series A financing. Subsequently led all early discovery efforts to build deep pipeline of first in class small molecule inhibitor programs. Vividion was acquired by Bayer Pharmaceuticals in 2021 for $2B, in recognition of its uniquely valuable platform and pipeline. Promoted to CSO of Vividion in early 2023.  Vividion was responsible for 3 small molecule clinical entries in 2023, two internally run trials (STAT3, and Keap1 activator/NRF2 inhibitor) and on partnered trials (Roche, WRN), and continues to grow and advance a deep pipeline of novel small molecule discovery and development programs. Author or co-author of more than 40 scientific publications, and 6 issued patents.

Lyn Jones



Speaker: Lyn Jones, Dana-Farber Cancer Institute

Talk title: Covalent Drug Development - Targeting Cysteine and Beyond

Biography: Lyn Jones completed PhD studies in synthetic organic chemistry at the University of Nottingham, before starting his postdoctoral research at The Scripps Research Institute, California in chemical biology. He joined Pfizer Sandwich (UK) as a medicinal chemistry team leader, eventually becoming Head of Chemical Biology and Lead Discovery Technologies. He transferred to Pfizer Cambridge (USA) to become Head of Rare Disease Chemistry and Head of Chemical Biology. He then helped establish Jnana Therapeutics as Head of Chemistry and Chemical Biology, before moving to his current roles as Director of the Center for Protein Degradation, Institute Scientist, and Principal Investigator at the Dana-Farber Cancer Institute in Boston. His research interests include the creation and application of chemistry-based technologies, such as covalent protein labeling modalities and induced-proximity pharmacology, with the objective of expanding the druggable proteome.

Monique Mulder 



Speaker: Monique Mulder, Leiden University Medical Center 

Talk title: Unveiling the Ubiquitin System through Covalent Enzyme Inhibition

Biography: Monique Mulder earned her PhD in Medicinal Chemistry at Utrecht University in 2012. Subsequently, she embarked on a trajectory that integrates chemical principles with cutting-edge biological techniques. She now leads the Mulder lab at Leiden University Medical Center, where her research is centered on elucidating the intricate mechanisms governing post-translational modifications of substrate proteins by ubiquitin and ubiquitin-like proteins. Her focus extends to understanding how dysregulation in these processes contributes to the pathogenesis of diseases like neurodegeneration and cancer, striving to illuminate the pathogenesis at a molecular level. The lab specializes in crafting tailored covalent small molecule inhibitors and chemical probes essential for unraveling the complexities of protein (de)ubiquitination. 

Megan Matthews


Speaker: Megan Matthews, University of Pennsylvania, USA

Talk title: The revolution and evolution of activity-based protein profiling

Biography: Megan received her BA in Chemistry from Miami University and her PhD from Penn State University under Marty Bollinger and Carsten Krebs. Her PhD work led to an understanding for how iron- and 2-oxoglutarate dependent oxygenases suppress hydroxylation to allow for halogenation and other outcomes important in natural product biosynthesis. Upon graduation, she performed postdoctoral studies at Scripps Research in the chemical biology laboratory of Ben Cravatt as a Helen Hay Whitney Fellow. Matthews investigated the prevalence of undiscovered protein-bound electrophiles and the (dys)functions that the unknown electrophiles impart, uncovering evidence for their involvement in cancer and diseases of the central nervous system. Her program is tracking down these and a host of other leads to novel disease biology and therapeutics.

 

We're excited to unveil our partnership opportunities! For more information on how to participate please download our - Partnership Prospectus 

If you have any questions or wish to connect with a member of the events team, please contact meetings@bps.ac.uk.
 


Fidabio assist you realizing the full potential of your complex biology beyond current technologies. We offer a completely new way to quantify and characterize complex biology in native conditions.  

Flow Induced Dispersion Analysis (FIDA) is a revolutionary, first principle technology for in solution, accurate and reproducible measurement of hydrodynamic radius of biomolecules in complex matrices leading to a wide range of orthogonal biophysics assays. 

It has been developed for quantification and characterization of proteins (including biologics) and particles with diameter from 0.5 to 1000 nm, including complex interactions, stoichiometry, oligomeric states etc. 

The FIDA technology is characterized by: 

•    Being fast (minutes)
•    Requiring very small sample amounts (nl-μl) 
•    Being exceptionally tolerant to the sample matrix. 

Contrary to most other procedures, the FIDA methodology is based on binding in homogenous solution; complications related to non-specific surface adsorption and challenging assay development is therefore avoided. 

The unique features of FIDA enable characterization and quantification in native (biorelevant) environments. In-built assay quality control ensures high data reliability and walk-away automation sets free resources for other tasks. 



Applied Photophysics of Leatherhead, Surrey, UK, is a leading provider of solutions for the biophysical characterisation of biomolecules and has been providing spectroscopy to the research community for over 50 years. Chirascan™ systems use the phenomenon of circular dichroism (CD) to characterise changes in the higher-order structure of proteins. These systems are used in cutting-edge research and to support the development of innovator drugs and biosimilars in the biopharmaceutical industry.

The company’s SX range of stopped-flow spectrometers is acknowledged globally as the gold standard for kinetic studies of fast biochemical reactions. Through a joint venture with Fluorescence Innovations Inc of Minneapolis, MN, USA, operating as Protein Stable, they have also introduced easy-to-use protein stability screening with microplate-based intrinsic fluorescence thermal ramping and chemical melt plate readers.


OmicScouts facilitates next generation drug discovery with its expertise in chemical proteomics. We provide end-to-end solutions and tailored projects integrating quantitative mass spectrometry and bioinformatics with biochemical and cell culture expertise. Our technologies enable comprehensive drug target deconvolution (target ID, selectivity, engagement), mode of action analyses and biomarker discovery. Founded by leading proteomics researchers, the company has a track record in delivering significant collaborations with top pharmaceutical and biotechnology companies.

Selvita is a preclinical Contract Research Organization providing multidisciplinary support in resolving the unique challenges of research within the areas of drug discovery and drug development studies. Selvita was established in 2007 and currently employs almost 900 professionals, of which over 40% hold a PhD degree. The Company research sites are located in Krakow (HQ) and Poznan, Poland, as well as Zagreb, Croatia. Selvita’s international offices are located in Cambridge, MA, and San Francisco Bay Area, in the U.S., as well as in Cambridge, the UK. 

Selvita Group has broad expertise and track record in oncology, inflammation, fibrosis, anti-infectives, respiratory diseases and CNS. The company offers drug discovery support at every stage of the early discovery phase up to the preclinical development. Selvita specializes in a variety of drug discovery processes from in silico drug design and synthesis of a target-focused library, SAR and ADME-driven lead optimization and toxicity prediction, followed by complex preclinical in vitro and in vivo pharmacology, structural biology, all tailored to the customer’s needs.


Genedata transforms data into intelligence with innovative software solutions that incorporate extensive biopharma R&D domain knowledge. Multinational biopharmaceutical organizations and cutting-edge biotechs around the globe rely on Genedata to digitalize and automate data-rich and complex R&D processes. From early discovery all the way to the clinic, Genedata solutions help maximize the ROI in R&D expenditure. Founded in 1997, Genedata is headquartered in Basel, Switzerland with additional offices in Boston, London, Munich, San Francisco, Singapore, and Tokyo.

Enzymlogic is a specialist CRO, providing kinetic profiling services for small molecule drug discovery with unparalleled speed and efficiency. We facilitate the screening of reversible and irreversible inhibitors in early discovery to iterate Med Chem, understand PK PD disconnects and build better models to define therapeutic windows.

Immerse yourself in a world of discovery at the renowned Discovery Centre in Cambridge! Join us for an exclusive event that celebrates innovation and exploration. Explore cutting-edge ideas and connect with industry leaders in this dynamic space known for fostering ground breaking discoveries. Mark your calendar for an unforgettable experience at the Discovery Centre in Cambridge!



Venue
The Discovery Centre
Biomedical Campus
1 Francis Crick Ave
Trumpington
Cambridge
CB2 0AA

Tickets


Early Bird Affiliate and Retired Non Member Ticket Non-Member Ticket £340.00
Early Bird Full and Retired Member Ticket Member Ticket £220.00
Early Bird Journal Author, Fellow, Retired Fellow, Honorary Fellow Member Ticket Member Ticket £220.00
Early Bird Undergraduate, Postgraduate, Affiliate, ECR and Diploma Student Member Registration Member Ticket £120.00
Early Bird Undergraduate, Postgraduate, ECR and Diploma Student Non-Member Registration Non-Member Ticket £180.00

Bharath Srinivasan

Principal Scientist, AstraZeneca, UK  

 

Bharath Srinivasan studied the structure-function relationship in members of the Haloacid Dehalogenase superfamily of enzymes as part of his PhD studies. He pursued an NIH-sponsored postdoctoral fellowship at the Centre for the Study of Systems Biology, Georgia Institute of Technology, working at the interface between biochemistry/biophysics, computational sciences and medicinal chemistry. Subsequently, he was awarded the prestigious Marie Skłodowska-Curie Actions fellowship to study the substrate specificity of deaminases acting on double-stranded RNA at the Instituto Gulbenkian de Ciencia, Portugal. Currently, Bharath is a Principal Scientist at the Mechanistic and Structural Biology Division at AstraZeneca, contributing actively to several oncology projects deducing the Mechanism of Action of small-molecule leads. Bharath has published around 40 peer-reviewed publications, 1 patent and several science outreach articles. He is an editor with two prominent pharmacology journals (British Journal of Pharmacology and Current opinion in Pharmacology), a faculty with facultyopinions and on the editorial advisory board of FEBS J. He is also an Honorary Associate Professor of Pharmacy and Life Sciences at the Robert Gordon University, Aberdeen. Further, he serves on the industrial committees of Biochemical Society and British Pharmacological Society. He is passionate about biophysical and kinetic characterization of enzymes with particular emphasis on studying the spatio-temporal evolution of kinetic systems, steady state kinetics, pre-steady state kinetics, single turnover kinetics, non-Michaelian kinetics and equilibrium/non-equilibrium modalities of enzyme inhibition. Bharath is also invested heavily in optimizing methods for in-cellulo kinetics and label-free detection methods. You can connect with him @ https://www.linkedin.com/in/bharath-srinivasan-b1716b3b/ or @ https://twitter.com/bharath_IGC.

Simon Lucas 

Associate Principal Scientist, AstraZeneca, UK 



Simon is a Medicinal Chemist with experience working on drug discovery projects at all stages. He obtained his PhD from the University of Strathclyde in 2019 through the GSK/Strathclyde Industrial PhD scheme where he worked in the Epigenetics group on the development of chemical tools for Bromodomain targets. He joined AstraZeneca in 2019 as a medicinal chemist in the Hit Discovery group where he has worked extensively on fragment-based lead generation and covalent hit identification projects delivering multiple lead series to project teams.

Mark McAlister 

Director, Mechanistic and Structural Biology, AstraZeneca, UK 



Mark McAlister is Director of Biophysics at AstraZeneca Cambridge UK. He obtained his PhD in 1993 from University of Aberdeen on the biochemistry of the complement C1, followed by postdocs at Oxford University and UCL on NMR structure and interactions of leukocyte cell-adhesion proteins. He then led the protein engineering lab at Bloomsbury Centre for Structural Biology (UCL/Birkbeck) contributing to 12 novel crystal structures and spin-out of Domainex Ltd. He joined AstraZeneca in 2002 to establish the protein engineering group, which he led until 2010 before moving to leadership roles in protein structure and biophysics. 
He is expert in protein biochemistry, biophysics and early drug discovery and has worked across a range of disease therapy areas, but with a focus on small-molecule cancer drug discover over the last 10 years, including project leadership and externalization. He leads the molecular biophysics group responsible for biomolecular NMR, structural mass spectrometry and biophysics and leads the AZ covalent hit discovery capability. He currently focusses on strategies to enable drug discovery for intractable or challenging oncology drug targets, including affinity-based screening, molecular glue strategies and electrophile-first covalent lead generation. 
 

Sarah Hewitt 

Senior Research Scientist, AstraZeneca, UK 



Sarah is a biochemist in the Mechanistic and Structural Biology group at AstraZeneca. This follows a PhD at the University of Leeds within the general remit of supramolecular chemical biology, and postdoc at Loughborough University developing real-time enzyme monitoring assays before moving to industry. She started at Vertex Pharmaceuticals in Oxford prior to moving to AstraZeneca in 2020. Sarah now focusses on using mass spectrometry for covalent hit finding and covalent hit to lead studies at AstraZeneca, developing the platform and contributing to many projects.  
 

Abstract submissions are scheduled to open on Monday, 4th March.
From
16 October 2024
To
17 October 2024
Delivery Method
In-Person Only
Venue
The Discovery Centre, Biomedical Campus, 1 Francis Crick Ave, Trumpington, Cambridge, CB2 0AA




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