What is the difference between a ‘chemical’ and a ‘drug’?

Lead Identification Phase in the Drug Discovery Process

Drug Discovery/Development Process

Basic Research

Discovery

Preclinical Development

Clinical Development

FDA Filing

Discovery Phase of Drug Development

Basic Research

Discovery

Preclinical Development

Target Identification

Target Validation

‘Hit’ Identification

Lead Series Generation

Lead Optimization

Safety Testing Before FIM

Currently Marketed Drug Targets

Current therapies are based on less than 500 molecular targets

Why Drugs Fail in the Clinic

Phase II failures 2008-2010

Lead optimization plays significant role in success of drugs

Efficacy Failures many times are “mechanism of action failures”

Discovery Phase of Drug Development

Target Identification

Target Validation

‘Hit’ Identification

Lead Series Generation

Safety Testing Before FIM

Lead Optimization

Start – with 1 million -Thousands- Tens -One/Two – Ending

Hit Identification Phase

High throughput screening of corporate deck to identify ‘Hits’.

Large corporate compound decks contain >1,000,000 compounds
Screen entire deck or carry out ‘focused’ subdeck screens depending on target
A hit is defined as a compound that exhibits a preselected level of activity against the target in the HTS assay
Each compound is tested in an assay for the target at single concentration (10 mM)

High throughput screening of corporate deck to identify ‘Hits’.

1536 well plates testing approximately 1500 test compounds per plate

Hit Identification Phase

Primary Hit:

Validated Hit:

Confirmed Hit:

Exhibit activity above threshold in primary screen at 10 mM
Exhibit activity in single point retest at 10 mM
Identity and purity of compound is confirmed
Compound shows a dose-dependent response CRC analysis
Compound shows little or no response in control assays
Ideal if related compounds in deck also show activity (not ‘singleton’) eg. >50% inhibition in a binding inhibition screen eg. Repeat at >50% inhibition in a binding inhibition screen
Optimal if compound shows activity in a ‘Secondary’ assay eg. Agonist shows activity in FLIPR and IP3 assay

Lead Series Identification

Hit Clusters:

From ‘Hits’, several ‘compound clusters’ may be identified by structure
Discovery team can select from these clusters to explore further
Analogues of the clusters can be chosen from corporate deck or for purchase for testing in primary assay
Medicinal chemists may begin to synthesize analogues based on hit structures -Compounds may be tested in single point or directly in CRC analysis – Single compound synthesis (1-5 compounds per round) – Parallel chemistry compound synthesis (10 – 500 compounds per round) – Typically a small group of chemists assigned to program to expand upon hits

Compound clusters expanded and explored to identify ‘Lead Series’

– Demonstrable and tractable Structure Activity Relationship (SAR) ‘Lead’ characteristics

– Demonstrable concentration-dependent activity at primary target

– Ease of synthesis. Chemically tractable scaffolds that are amenable to analogue generation

– Prior art has been searched, a clear intellectual property path has been identified and the competitive landscape is understood

– Minimal activity at primary off–target and/or SAR for off-target activity tractable Once several lead series are identified with tractable SAR

– Full complement of Medicinal Chemists is added and the project advances to full-program status

Goal of Lead Optimization Phase

– What are ‘drug-like’ properties ? Deliver a compound suitable for testing in Humans

– Multiple properties are required to be optimized for when working toward a clinical drug candidate?