usugm 2014 - jinling sui (flately discovery): building the bioinformatic platform for drug...
TRANSCRIPT
Building An Informatic Platform
for Small Molecule R&D
Jinliang Sui, M.D., Ph.D.
Vice President
R&D Technology
Flatley Discovery Lab
Sep 2014
2
Cystic Fibrosis
Genetics: autosomal recessive mutations on the gene of Cystic Fibrosis
Transmembrane Conductance Regulator (CFTR). Most CF patients (>70%)
carry the dF508 mutation
Patients: ~ 30,000 in US; 70,000 worldwide; carriers : 1/31 Americans (>10 Mil
total), 1/28 Caucasians
Cellular mechanisms: CFTR-dF508 protein is deficient in trafficking to the
plasma membrane and in CFTR gating activities related to Cl- secretion,
resulting in deficiency of water secretion
Affected organs: all organs with epithelial cells on the surface are affected;
most importantly lungs, pancreas, skin, productive organs
Symptoms: salty sweat, excessive appetite but poor weight gain, coughing,
pneumonia, and lung failure
Life expectancy: Increased from 4 yrs (1960) to >37 yrs with improved
treatments
Cystic Fibrosis
Flatley Discovery Lab LLC 10/2/2014
Our mission is to conduct and promote the discovery of new and efficacious treatment for Cystic fibrosis
Incorporated in June 2009, privately funded by the Flatley Foundation
HTS started August 2010
Screened >1,000,000 new compounds in singleton
Screened >40,000 paired combinations
Clinical development candidate FDL169 (CFTRdF508 primary corrector) nominated in Oct 2013; clinical trial will start at the end of 2014
Clinical development candidate FDL438 (CFTRdF508 synergy corrector) nominated in Sep 2014
Flatley Discovery Lab LLC 10/2/2014
Flatley Discovery Lab
Data Management Goals
Capacity for HTS data:
40,000 data points per day
Time-course kinetics non-linear regression analysis
Capacity for Chemistry
Focused on small molecules
Up to 2 million compounds
Small to medium size user group (10-20 users)
Key Functions
Compound registration, limited inventory and SAR
HTS raw data transformation and data QC
Compound profiling & HTS data report
Non-HTS data: electrophysiology, ADME, In Vivo
Flatley Discovery Lab LLC 10/2/2014
ChemFinderregistration, search,
profiling
The Build-Up Phase
(2010)
AccessHTS data
process & QC
Excel AppHTS data
transformation
Plate ReaderRaw data in plain
text format
SDF/Excel from chemical
vendors
AccessHTS data
process & QC
AccessHTS data
process & QC
AccessHTS data
process & QC
ChemFinderregistration, search,
profiling
ChemFinderregistration, search,
profiling
ChemFinderregistration, search,
profiling
AccessHTS data
process & QC
ChemFinderregistration, search,
profiling
Access AppHTS data
process & QC
ChemFinderregistration, search,
profiling
Years Later
(2014)
Access AppHTS data
process & QC
ChemCartregistration, search,
profiling/report
Excel AppHTS data
transformation
Plate Reader(s)Raw data in plain text
format
SDF/Excel from chemical
vendors
Oracle
SQLJChem
Cartridge
VortexSAR analysis, report,
visualization
Pipeline PilotSAR analysis,
visualization, data mining
Flatley Discovery Lab LLC 10/2/2014
Plate map
ID, location, [c]Plate map
ID, location, [c]Plate map
ID, location, [c]Plate map
ID, location, [c]Plate map
ID, location, [c]Plate map
ID, location, [c]Inventory map
HTS Data Workflow (I)7
Plate
Reader
Assay
plateAssay
plateAssay
plateAssay
plateAssay
plateAssay
plates
Raw dataRaw data
Raw dataRaw data
Raw dataRaw dataRaw data set
Treatment
records
(meta data)
HTS Data Master
(HTS data QC)
Compound
plateCompound
plateCompound
plateCompound
plateCompound
plateCompound
plates
Exp
erim
ents
OracleP
late
map
Raw
data
&
results
Flatley Discovery Lab LLC 10/2/2014
8
ChemLib-01
ChemLib-02
ChemLib-03
ChemLib-04
HTS Data-01
HTS Data-02
ChemLib-05
ChemLib-06
HTS Data
Master
HTS Data-03
HTS Data-04
HTS Data-05
HTS Data-06
Compound inventory HTS data (source) HTS data (local)
Assay plate data
Assay plate data
Assay plate data
Assay plate data
Assay plate data
Assay plate data
Assay plate data
Assay plate data
Assay plate data
Data
Bank
Meta data
Oracle
Central data (current version)
Data
wa
reh
ou
se
Central data (desktop version)
HTS Data Workflow (II)
FDSS Data
Export FDSS Data
Export
Exp-Day1
Exp-Day2
Kinetic
Analysis
(Excel)
Import raw data &
meta data
Review imported
plate set
Control data QC
Data transformation
& auto QC
Flag disqualified
plates
Plate quality review
Calculate compound
treatment data
Compound data
QC
Data warehouse
Compound data
aggregations
Update progress
report
Missing data point
analysis
Create make-up
plate listMakeup screen request
HTS Data Workflow (III) 9
Metadata revision
Oracle
Flatley Discovery Lab LLC 10/2/2014
ChemCart Report 10
Grouped result list
Level-I data
Level-II data
Dose-response
plot based on
Level-II data
Flatley Discovery Lab LLC 10/2/2014
ChemAxon
Structure Search
& Display
Summary1) A suitable bioinformatic platform is critical to ensure for small molecule R&D, especially
for high throughput screen; great informatics experts are equally important as great
scientists
2) Desktop-based apps can be built quickly to meet the need of early stage R&D, while
suitable commercial packages are being identified and implemented
3) There is no perfect commercial package for everyone; tailored package plus home-
built apps is often the best solution at the end
4) Expectations must be curtailed, checked, and tested rigorously when evaluating
commercial packages; implement and meeting user’s specifics take time
5) ChemCart (DeltaSoft) is the easiest registration and browser application to implement
and use at FDL
6) Marvin and JChem Cartridge (ChemAxon) provides robust search, display, property
calculations, and performance on >1,000,000 compounds
7) Vortex (Dotmatics) has been the most versatile app for complex data visualization
Flatley Discovery Lab LLC 10/2/2014
Acknowledgement
Jon Patterson (ChemAxon)
Yvonne Shimshock & Jim Bullington (DeltaSoft)
Jesse Gordon (Dotmatics)
Paul Weiner (FDL)
Flatley Discovery Lab LLC 10/2/2014
Abstract
Building a bioinformatic platform is challenging for small biotech startups withlimited resource. At Flatley Discovery Lab (FDL), we started with desktop-based applications for processing HTS data and managing chemical librariesin the ‘build-up’ phase, followed by implementing commercial informaticspackages. Our platform is tailored to our specific need: with industrialstandard Oracle data backbone, the desktop-based components became thefront-end apps for raw data process, serving biology specific protocols andformats. Advanced data analysis and visualization tools were recentlyintroduced to support our SAR and development need.
In 5 years since its inception, FDL has produced several exciting CFTRmodulators into our drug development pipeline towards efficacious treatmentfor Cystic Fibrosis. Our experiences have taught us that a success in drugdiscovery R&D relies heavily on a productive informatics platform supportingall the scientific and development efforts
Flatley Discovery Lab LLC 10/2/2014