Week 8

• Drug Discovery Process

  1. Target identification and validation

  2. Pathway analysis

  3. GWAS for target ID and drug repositioning
• Pharmacogenetics

  1. Right Drug, Right Dose, Right Patient

  2. PGx can enhance drugs (more competitive “products”)

  3. Increase power of clinical trials

  4. Understand key ADME and PK/PD mechanisms
• Complex Disease Targets

  • Too Long in Body
  • Adverse Reactions
  • Poor Absorption
  • Low Levels in Body
  • Not Effective Enough
  • Not Sufficiently Selective
  • Side Effects
  • Unsafe
  • Unstable
  • Competition
  • Impractical To Make
• Most compounds do not become medicines
• Making Drugs: The Innovation Challenge

  1. Target ID and Validation

  2. Hit and Lead ID

  3. Lead Optimisation

  4. To Candidate

  5. Phase I

  6. Phase IIa & b

  7. Phase III & Market
• Phase III & Market

  1. Large comparative study (compound versus placebo) in 1000s of patients to establish clinical benefit & safety

  2. Drug launch and subsequent safety surveillance

  3. Mechanism insight for Pharmacovigilance

  4. Rare variants causing adverse events may emerge
• Phase II

  1. (IIa) Determine therapeutic dose

  2. (Iib) Evaluate drug efficacy to achieve POC

  3. Conducted in 100-200 patients

  4. Common variants may impact efficacy

  5. Disease endotypes as stratifiers
• Phase I


  1. Evaluate clinical pharmacology of candidate drug in 20-100 healthy human volunteers

  2. Anticipate common adverse events based on expression and pathway knowledge
• Lead to Candidate


  1. Medicinal chemistry to optimise lead properties

  2. Backup lead

  3. Evaluate drug pharmacology in preclinical model

  4. Evolutionary analysis to predict fidelity of animal models
• Target ID & Validation

  1. Identification of drug targets based on biological rationale and known small molecule tractability

  2. Target validation based on Omics

  3. Druggability and tractability prediction
• Hit and Lead ID

  1. Configure & run high throughput screen to ID bioactive small molecules

  2. Identify drug-like lead molecule(s)

  3. Define cross screening variants

  4. Mechanistic models
• Genomics in the Drug Discovery Process: This process relates to small molecule drugs. Biologic preclinical development is shorter
• Perspectives on target validation and safety

  • Biology
  • Variation
  • Similarity
  • Tractability
  • Robust Assay
• Paracelsus: '"All things are poison, and nothing is without poison; only the dose permits something not to be poisonous"'
• The Target Discovery & Validation Process

  1. Clinical Samples

  2. Cell Models

  3. Genomics

  4. Proteomics

  5. Genetics

  6. Modulation in Animal Models
• The drug design process is iterative, with multiple rounds of synthesis and testing.