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Hit and Lead Discovery in an Academic Setting. Julie Frearson Iain Collie University of Dundee. Introduction. The facility Current approaches & technologies Progress. A unique, fully integrated drug discovery team within a world class research environment. DDU. Drug Discovery Unit.

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Hit and lead discovery in an academic setting

Hit and Lead Discovery in an Academic Setting

Julie Frearson

Iain Collie

University of Dundee

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Introduction
Introduction

  • The facility

  • Current approaches & technologies

  • Progress

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


A unique fully integrated drug discovery team within a world class research environment
A unique, fully integrated drug discovery team within a world class research environment

DDU

Drug Discovery Unit

College of Life Sciences

University of Dundee

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Sir james black centre
Sir James Black Centre world class research environment

Screening laboratory with modular workstation layout

The recently constructed James Black Centre housing, on level 1, the Drug Discovery Unit

www.drugdiscovery.dundee.ac.uk

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Vision mission key objectives
Vision, Mission, Key Objectives world class research environment

Vision

To be an internationally recognised drug discovery group and partner of repute for the biopharmaceutical sector in developing new therapeutics for unmet need

Mission

To increase the efficiency and success of translating life sciences research into therapeutic application

Key Objectives

To translate basic biomedical research into candidate medicines for neglected diseases

and

To vastly improve intellectual property positions on novel therapeutic targets through small molecule discovery

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Primary activities
Primary Activities world class research environment

Novel

Targets

& Pathways

Neglected

Diseases

DDU

Hits &

Leads

Leads & preclinical

candidates

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Drug Discovery @ Dundee world class research environment

  • Total Funding over 5 years: ~£12m

  • ~67% Wellcome Trust

  • Remainder from

    • Scottish Funding Council

    • Scottish Enterprise

    • ITI Life Sciences

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Key successes
Key Successes world class research environment

Target Prioritisation

384 MTS/HTS Robotics

Standard readouts

Validation

Druggability

Assay Feasibility

Toxicity

Resistance potential

Structural Information

Compound Sets

in vitro models

in vivo models

DMPK

Data Management

Medicinal & Computational Chemistry

Structural Biology

  • Created a small Biotech style drug discovery group

  • Operational within 4 months of opening

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Key successes1
Key Successes world class research environment

  • Created a small Biotech style drug discovery group

  • Operational within 4 months of opening

  • Creation of purpose designed compound libraries

    • >97,000 compounds: diversity, bioactives, gene family focused

  • Prosecution of 18 target or phenotypic screens through hit discovery

  • 7 projects through hit to lead

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Ddu portfolio nov 2008
DDU Portfolio Nov 2008 world class research environment

Nonsense mutation read through agents

Stem cell modulation agents

Numerous campaigns

Target

validation

Assay

Development

Hit

Discovery

Hit

Validation

Hits to

Leads

Lead

Optimization

Sugar

dehydrogenase

De-N-acetylase

PS-Q series

Focussed kinase set phenotypic screen hits

Phenotypic screening hit

N-Myristoyl-

transferase

Kinase

Kinase

Chemical target validation

PK4

KPS Series 01

Kinase

RNA Ligase

Chemical target validation

GSK

GSK 07

Kinase

Viral protease

PK50

Chemical target validation

Replication licensing inhibitors

Trypanothione

synthetase

Chemical target validation

Phosphatase inhibitors

NFκB repressor

RNAi screen

Fungal targets 2,3,4

SUMO repressor RNAi screen

miRNA regulator RNAi screen

Studies on hold and project returned to originating lab to address no go issues

PTR1/DHFR

UDP-Glc-4’-

epimerase

CRK3

UDP-GlcNAc

diphosphorylase

Trypanothione

reductase

Fungal Target 1

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Key successes2
Key Successes world class research environment

  • Created a small Biotech style drug discovery group

  • Operational within 4 months of opening

  • Creation of purpose designed compound libraries

    • >97,000 compounds: diversity, bioactives, gene family focused

  • Prosecution of 18 targets/phenotypics screens through hit discovery

  • 7 projects through hit to lead

  • Advanced leads developed

    • Series curing trypanosomiasis in mice

    • Series under investigation in cancer xenograft models

  • First group to be routinely screening in high throughput using hES cells

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Balanced Approach to Hit Discovery world class research environment

P. falciparum

T. brucei

Molecular Target

hES cells

keratinocytes

  • Diverse and flexible approach to lead discovery

  • Not limited to any one technology or target bias

  • Polypharmacology required for good & sustained efficacy?

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Drug discovery for tropical diseases initiative ddtdi goals

Drug Discovery for Tropical Diseases initiative (DDTDi) world class research environment- Goals

To deliver at least 1 drug candidate for human African trypanosomiasis (HAT) for entry into formal pre-clinical development by March 2011

To deliver high quality lead series for neglected diseases suitable for progression into lead optimisation in-house or by partner organisations

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Tropical Infectious Disease Burden world class research environment

  • 35,000 deaths per day in developing world

  • Many of the deaths preventable

  • Many current drugs need to be replaced due to toxicity, cost, emerging resistance, suitability to use in the developing world

  • Health care budget in Sub-Saharan Africa

    • $13 per capita per year

  • No commercial market to offset ~$800m cost and risk to develop new drugs

  • The solution does not lie solely with the commercial sector

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Ddtdi strategy

DDTDi world class research environment Strategy

Work in collaboration with academic, industrial and PDP partners

Engaging in small focussed consortia to enable Drug Discovery for kinetoplastids from target to clinic

Co-ordination with DNDi and SGC for lead generation

Aligning ourselves with major downstream partners

DNDi

MMV

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Gene family approach
Gene Family Approach world class research environment

Kinases

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Kinases as drug targets for t brucei
Kinases as Drug Targets for world class research environmentT. brucei

  • Known druggable targets

  • Increasing genetic evidence of essentiality of kinases in trypanosomes and other parasites

  • Evidence of inhibitor selectivity between T. brucei and human homologues

  • Non-selectivity within tryp kinases an advantage

  • Acute dosing regimen for HAT could limit toxicity concerns

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Ddtdi strategy1
DDTDi Strategy world class research environment

  • Developed focused kinase library

    • ~ 5000 compounds

    • >150 scaffolds with even representation

  • Tackle known genetically validated kinases in parallel

    • Collaborate with expert biology groups

    • Multiple kinase enzyme assays in parallel

  • Phenotypic screening against T. brucei, malaria and TB in vitro

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


world class research environment

Kinase Targets Under Investigation

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


TbGSK3 world class research environment

PI > 50%

87 cpds

TbPK4

PI > 50%

65 cpds

1

cpds

12

cpds

10

cpds

TbPK50

PI >50%

77 cpds

Kinase Target Selectivity

PK4: 70% confirmation rate

Final hit rate 5.4%

PK50: 91% confirmation rate

Final hit rate 12.8%

TbGSK3: 91% confirmation rate

Final hit rate 12.6%

GSK3 project advanced

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Target vs. parasite proliferation world class research environment- correlation?

Lifting the Lid on Academic Laboratory Automation

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Lack of trypanosome activity
Lack of trypanosome activity world class research environment

T. brucei potency pEC50

T. brucei potency pEC50

CRK3 potency pIC50

CRK3 potency pIC50

No evidence of Leishmania in vitro activity either (Mottram et al.)

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Kinase set phenotypic screen
Kinase Set Phenotypic Screen world class research environment

  • Screen

    • Kinase Set

    • 3,885 compounds

    • 121 compounds progressed to potency

  • Multiple series

    • <1µM EC50

    • >10-fold selectivity

    • Best

      • T. brucei EC50 20nM

      • MRC-5 EC50 >50M

    • Following up in chemistry and DMPK

    • Investigating Serenex, Cellzome technology to identify potential targets

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


N-Myristoyl Transferase world class research environment

Project Leaders: Stephen Brand, Stuart McElroy

Debbie Smith (York) – Parasitology, Mode of action studies

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


NMT Introduction world class research environment

  • Catalyses the transfer of myristate from MyCoA to the N-terminal glycine NH2 of potentially >60 target proteins

  • Myristoylation important for localisation at membranes and/or activation

  • Strong biological + chemical evidence for NMT being a viable target

  • Screened 63,362 compounds within DDU

  • Identified one key compound series (5 examples <20μM)

  • Hit validation: DDD00064558 resynthesised and retested

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Summary so far world class research environment

  • Identified sub nanomolar inhibitors of T. brucei NMT and T. brucei proliferation in culture

  • Good correlation - NMT IC50 and T. brucei activity

  • Selectivity over human enzyme (>100-fold) reflected in selectivity vs. MRC5 growth assay (>1000-fold)

  • Enzyme kinetics in line with proposed NMT Bi Bi mechanism

  • Cidal mode of action

  • Reduction of activity vs. T. brucei on 20-fold over- expression of TbNMT

  • Inhibition of protein myristoylation without inhibition of protein synthesis

  • Binding mode confirmed by X-ray structure

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Good affinity achieved and early selectivity driven by varying off-rates

HsNMT1

TbNMT

Lifting the Lid on Academic Laboratory Automation

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Pharmacokinetics of DDD00085646 varying off-rates

Oral pharmacokinetics of DDD00085646; good exposure at 50mg/kg

Cmax 6712 ng/ml

Tmax 2 hours

T1/2 2.0 hours

AUC0-T 22 µg.h/ml

EC90 (free)

EC50 2nM (~1ng/ml)

Fraction unbound 0.11 (89% ppb)

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Efficacy in mouse model of acute african sleeping sickness
Efficacy in mouse model of acute African sleeping sickness varying off-rates

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Conclusions
Conclusions varying off-rates

  • Balanced approach of molecular target and phenotypic screening vital in a drug discovery-immature area

    • Need robust assays & systems to support both approaches

    • Series of secondary assays to support target deconvolution

  • Particular success experienced with a molecular target leading to pleiotropic effects

    • Toxicity issues manageable – short term treatment?

  • Phenotypic hits may well be affecting multiple targets and therefore less susceptible to rapid resistance development

  • Efficient way forward for Neglected Disease Drug Discovery

    • Build up chemistries for druggable gene families and cross organism molecular targets to allow therapeutic switching

    • Leishmaniasis, Chagas, malaria etc.

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Interactions
Interactions varying off-rates

  • CRK3 - Jeremy Mottram (Univ. of Glasgow)

  • NMT - Debbie Smith (Univ. of York)

  • PK4, PK50,PLK - Tansy Hammarton (Univ. of Glasgow)

  • GSK3 - University of Washington; GSK

  • Quinols - Malcolm Stevens (Nottingham); Pharminox

  • Kinase Phenotypic Screening - Swiss Tropical Institute

  • Compound sets – Imperial College London, MRCT, WEHI, Max Planck (Dresden)

  • Companies – GlaxoSmithKline, Pfizer, Pharminox, Genzyme, Schering-Plough Scotland, BioFocus DPI, Vernalis, iTi Life Sciences

  • PDPs – DNDi, MMV

  • Drug Discovery Consortium – MRCT, CRT, ICR

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Acknowledgements
Acknowledgements varying off-rates

Core Group: Daan van Aalten, Ruth Brenk, Alan Fairlamb, Mike Ferguson, Julie Frearson, Ian Gilbert, Andrew Hopkins, Bill Hunter, Kevin Read, Paul Wyatt

Lifting the Lid on Academic Laboratory Automation

Hinxton Hall, Cambridge


Lifting the Lid on Academic Laboratory Automation varying off-rates

Hinxton Hall, Cambridge


Lifting the Lid on Academic Laboratory Automation varying off-rates

Hinxton Hall, Cambridge


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