Drug discovery stage definitions and compound characterisation guidelines

Target discovery

Demonstration that a potential target is present in human tumours and the identification of correlations between the presence or absence of the target in clinical material and clinical outcome.

Target validation

Proof-of-principle studies to show that modulation of the target in model systems has the required effect on tumour biology. It may involve genetic or pharmacological manipulation of the putative target leading to an appropriate in vitro(or in vivo) phenotypic response.

Hit identification

Identification of a small molecule with activity against the target. Hits may be identified through one or more hit identification approach, e.g. diversity screen; focussed screen (virtual followed by biochemical screen); fragment based screen; knowledge based (i.e. from literature or in house start point); de novo structure based design, etc.

Hit validation

Demonstration that the hit has the potential for modification to an entity with properties suitable for clinical use. A validated hit should ideally show the following characteristics:

  • Activity confirmed by retesting a fresh sample of confirmed structure and ≥90% purity (by HPLC)
  • * IC50/Ki ≤10µM in functional/biochemical assay
  • Specificity for target in selected assay format&
  • >10 fold selectivity against key undesired target(s) (may be a related target family member)
  • Some SAR apparent from available analogues (within screening collection, from commercial sources or newly synthesised)
  • Synthetically amenable to enable ready development of SAR
  • No obvious undesirable chemical features
  • Predicted physicochemical properties and ADME profile
  • * IC50/Ki requirement may vary dependant on the nature of the specific target

Lead identification

Identification of one or more lead small molecule chemical series, with confirmed potential to be developed into a clinical candidate during the lead optimisation stage

A confirmed lead series should ideally show the following characteristics and have collected the following data:

  • * IC50/Ki ≤1µM in functional/biochemical assay
  • >30 fold selectivity against key undesired target(s)
  • Functional cellular activity (IC50 ≤10µM) with SAR correlating with isolated target activity (i.e. confirmed mode of action)
  • Demonstrable SAR apparent from newly synthesised and/or commercially sourced analogues (i.e. key pharmacophic elements defined)
  • Experimentally derived in vitro ADME profile (e.g. CYP P450 inhibition, ideally IC50 >10µM; rodent and human microsomal clearance; aqueous solubility, ideally >10µM; permeability; hERG (binding), ideally IC50 >10µM, etc.)
  • Experimentally derived in vivo ADME profile of exemplar(s) from the lead series in order to assess potential liabilities (e.g. oral bio-availability, half-life, blood/plasma clearance, etc.)
  • Chemically tractable (suitable for the ready synthesis of analogues)
  • No obvious undesirable chemical features
  • Clear IP position
  • Chemistry strategy in place to address any potential liabilities
  • * IC50/Ki requirement may vary dependant on the nature of the specific target

Lead optimisation

  • Target potency suitable to deliver efficacy in an in vivo model at a (predicted) clinically achievable exposure; * typically IC50/Ki ≤10nM in functional/ biochemical assay
  • >100 fold selectivity against key undesired target(s)
  • Functional cellular activity (typically IC50 ≤1µM) correlating with isolated target activity (i.e. confirmed mode of action)
  • Acceptable experimentally derived in vitro ADME profile (e.g. CYP P450 inhibition profile, IC50 >10µM; no CYP P450 time dependency; rodent and human microsomal clearance; aqueous solubility; permeability, etc.)
  • Efficacy demonstrated in (ideally) two in vivo models at clinically achievable exposures using pharmaceutically acceptable dosing vehicles and supported by a translatable mechanistic biomarker
  • In vivo DMPK profile suitable for proposed route of administration and clinical dosing regimen (e.g. bioavailability, half-life, blood/plasma clearance etc.)
  • PK/PD assessment based on efficacy and biomarker outcomes
  • Extended selectivity profile and preliminary toxicology assessment (e.g. hERG (functional assay), MTD in efficacy study)
  • A viable, reproducible synthetic route to support synthesis of multi-gramme quantities of crystalline drug substance
  • Assessment of solid and solution state stability (parent and/or salt)
  • IP position supported by filed patent(s)
  • * IC50/Ki requirement may vary dependant on the nature of the specific target

Clinical candidate development

Preclinical development studies required for the initiation of clinical studies, e.g. bulk synthesis/manufacture to GMP, toxicology to GCP, biomarker development and validation etc