ANTIPARASITIC DRUG DISCOVERY USING A HYBRID OPEN MODEL
19 November 2013 – BAARN Meeting
Michael Pollastri, Ph.D.,
Department of Chemistry & Chemical Biology
Northeastern University
617.373.2703
www.northeastern.edu/pollastri
Neglected diseases A serious healthcare disparity
• Diseases that affect the poorest in the world • Only 10% of healthcare and research spending is directed
towards 90% of the population – 1975-1999: 13 out of 1,398 new drugs for NTDs – 2000-2011: 37 out of 850 (4%), including :25 repurposed products
or new formulations, and 4 NCEs (1%)
Why?? Because the “blockbuster model” doesn’t apply to diseases that
are endemic among the very poor
Note, total spend in 2011 for 31 NTDs was $3.05 billion 2011 PFE R&D spend: $9 billion.
Trouiller et al 2002 Lancet 359:2188-2194
Pedrique et al 2013 Lancet ASAP
The result of the neglect: Current pharmacopeia for sleeping sickness
Drug First used Toxicity
Suramin 1920 Anaphlaxis, renal failure, neuro effects
Pentamidine 1940 Hypotension, hyper- or hypo-glycemia
Melarsoprol
1949 Death (5%), reactive encephalopathy
Eflornithine 1981 Bone marrow toxicity, seizures,
Is it worth patenting for NTD drugs?
• DNDi, MMV do not require an IP position (freedom-to-operate is important, though)
• Costs of filing/maintaining patents may not be proportional to benefit
• Patenting may also delay sharing of data in an acutely resource-poor research area
Washington U., STL
Stephen Beverly
Matt Kuhlmann
WRAIR
Rick Sciotti
Norma Roncal
GlaxoSmithKline
Pepe Fiandor
Pili Manzano
Silvia Gonzalez
Julio Martin
Manuela Berlanga
David Drewry
Bill Zuercher
University of Georgia
Kojo Mensa-Wilmot
Paul Guyett
Ranjan Behera
CSIC – Granada, Spain
Miguel Navarro
Rosario Diaz-Gonzalez
New York U
Ana Rodriguez
Cristina Galen Rodriguez
Southern Methodist University
Larry Ruben
Vidya Pandarinath
AstraZeneca
Peter Webborn
Mark Wenlock
Kevin Pritchard
Seattle Biomed
Ken Stuart
Igor Cestari
Chris Merritt
Marine Biological Lab
Bob Campbell
Nick Bland
Vanderbilt Universiy
Galena Lepesheva
NORTHEASTERN UNIVERSITY
Laboratory For Neglected
Disease Drug Discovery
Data in a distributed drug discovery model Evolution of need, 2007-2013
A flexible data system was needed
Desired criteria
– Chemist-proof
– Low maintenance
– Ability to import/export data easily
– Low cost
Capabilities
– Compound registration
– Biological data import
– Computed properties
– Selective data sharing with public and collaborators outside NEU
(Excel is not a data system, by the way)
Collaborative Drug Discovery A cloud-based solution
Courtesy of Collaborative Drug Discovery
Medicinal chemistry An iterative process
• Registration & Data upload via .csv • Data download via .csv, .xls, or .sdf
Synthesis Screening
Analysis Design
Compound registration
Biological & ADME Data
Upload
Data Download
Third-party computational Third-party computational
and visualization tools
Collaborative Drug Discovery Vault
Courtesy of Collaborative Drug Discovery
Collaborative Drug Discovery Vault
Courtesy of Collaborative Drug Discovery
Data sharing in NTD drug discovery
Expanding R&D Efforts
New antiparasitic approaches
New compounds
& data
Guided by clear guidance on research
priorities and targeted product profiles
Utilizing new understanding of pathogen
targets and pathways
Leveraging publically released
compound sets and data
Increasing numbers of NTD drug discovery efforts: a GOOD thing, but let’s not waste efforts with duplication!
A range of data sharing scenarios
Fully Open
• Completely open to anyone
• Transparent, public data sharing
• Sharing of all details in real time
In the middle…
• Data is shared with an expanded group of teams
• Sharing of most critical details
• Sharing of resources & models
• Advising each other
Fully Closed
• Confidential
• Data is disclosed upon publication
• Legal agreements abound
• Works well for resource-rich environments
Pharma OSDD Malaria
http://openwetware.org/wiki/Open_Source_Drug_Discovery_-_Malaria
Northeastern
Initiative Members Confidential Knowledge Store
A “hybrid” open model of discovery
File Share • Models • Slides
Database • Structures • Screening data • ADME data • Public data sets
Member Lab 1 (Chemistry)
Chemical structures
Member Lab 2 (Biology)
Screening
Member Lab 3 (Modeling)
Models
Industrial partner (data)
ADME, Tox, selectivity
Targeted Product
Profiles for each
pathogen
Resources for key tasks
Stakeholders (DNDi, MMV etc)
Public data
Formal Launch Dec 1 2013! Crowdfunding campaign
ongoing!
Some details…
Ground rules • All data in the vault is a
confidential disclosure to consortium members.
• Participants must disclose all their data (including structures) in real time.
• There will be no lurking. We are not… • Trying to coordinate or
consolidate efforts, only to inform them
• Forcing collaborative efforts • Looking to rip anyone off.
Advantages • A “safe” venue for sharing and
discussing data and gaps • A framework to constructively
share “negative” data • Ability to bring in public data
automatically, and to publically share data when ready
• Opportunities to quickly identify complementary and/or redundant efforts
• Opportunities to cross-fertilize across other parasites
Get people hooked!
Seeding the database • All compounds & data
from NEU NTD work – Includes HTS hits for T
brucei from NEU-CSIC-GSK
• Developing mechanism for funding critical gap-filling experiments
• Constructing a kinase-targeted screening set for initiating parasite drug discovery projects
Next steps
Challenges • “You first” attitude is
slowing adoption • Funding • Different “phenotypes” of
researchers with varying comfort
• Uncharted waters in terms of intellectual property and innovation in drug discovery
Michael Pollastri, Ph.D.,
Department of Chemistry & Chemical Biology
Northeastern University
617.373.2703
Crowdfunding campaign: bit.ly/FightNTDs
Lab website: www.northeastern.edu/pollastri
Twitter: @NUTrypKiller
Global Health Initiative: www.northeastern.edu/globalhealth
