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

Vortex Visualization 11

Flatley Discovery Lab LLC 10/2/2014

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