PROJECT TYPE:
Compound testing scheme for identification and characterization in support of therapeutic development.
- Requirement of target selected and established hypothesis/evidence for validity in disease context.
- Goal is testing cascade for triage and characterization of compounds and collection of compounds suitably characterized for subsequent studies.
- Milestones to reflect assay readiness to support high throughput screen, compound triage and characterization for activity against primary target, specificity against relevant off-targets, cellular target engagement, cellular functional/phenotypic activity; appropriate activity of positive and negative controls in all assays; loss of activity in cellular systems lacking functional target.
- Milestones to support small molecule therapeutic development to include preparation and validation of chemical matter including confirmation of structure, purity, chemical stability/reactivity, assessment of physicochemical properties in vitro and in silico (including lipophilicity, polar surface area, solubility, permeability and efflux), initial assessment of in vitro ADME/PK characteristics such as plasma protein binding, microsomal metabolism/stability, induction of metabolic enzymes and affinity for transporters.
PROJECT TYPE:
Development/validation of pharmacodynamic and/or in vivo efficacy animal model
- Requirement is translational rationale, pre-clinically validated target and in vitro measures of target engagement and functional/phenotypic response and well-characterized in vivo probes. or other suitable means of target perturbation (CRISPR, etc)
- Goal is demonstration of dose-dependent in vivo PD/efficacy response quantitatively related to target engagement suitable for supporting in vivo optimization program.
- Milestones to reflect readiness to support in vivo PK/PD-driven compound optimization including relevant activity of positive/negative controls, adequate dynamic range and reproducibility for differentiation; appropriate correspondence demonstrated for target engagement versus efficacy.
PROJECT TYPE:
Pharmacodynamics and/or in vivo efficacy study
- Requirement of validated/characterized animal model and pharmacodynamics measure (both functional and target engagement), testing protocol and well-characterized therapeutic agents.
- Goal is well characterized early stage in vivo validated agents suitable for lead optimization.
- Milestones to reflect readiness to progress to lead optimization for small molecule therapeutic or biologic including pharmacokinetics that would allow adequate systemic free drug concentration in relevant compartment/tissue to support therapeutic hypothesis, biophysical characteristics that support further optimization against target access, duration of action and intended route of administration.
