Lecture 8 - Target validation Flashcards
what is target identification and validation?
Target Identification is the process by which a biological rationale for an approach is established and a putative target molecule (e.g. protein or nucleic acid) is identified as being of potential importance in the modulation of disease
Target Validation is a continuation of this process by which the predicted molecular target is shown to be linked to disease and relevant assay systems are developed to support the identification of initial ‘hits’ or chemical starting points prior to further optimization
what is a target ?
Drug targets are mainly Proteins (receptors, enzyme or channel) or in some cases nucleic acids (DNA or RNA).
They are biological molecules which regulate processes fundamental to the biology of the target disease.
It is the biomolecule which can be targeted in order to elicit a favorable disease outcome through modulation of its biological activity.
what is the rational for a good or right target ?
Efficacious – it’s modulation (e.g. inhibition or activation of activity) should ameliorate aspects of the disease presentation or progression
Safe – modulation of the target should not cause significant side effects
Relevant to clinical and commercial needs (see last lecture)
Allow for an assay cascade to be constructed
‘druggable’ –a multifaceted concept based on prior art, structural information, accessibility of the target etc. This is an evolving concept, but usuallyestimated by classifying it with known gene families or molecular features that have previously been successfully targeted with drugs
what is considered for target identification: selecting the right target
what are the ysmtopsm and physiology of the disease wished to treat?
what ohsyioloical or cellular signalling systems are known to be involved or perturbed in the disease?
is there a eugenic factor in the disease?
are here known biological systems or competitor approaches which can modulate disease progression ?
what is phenotypic drug discovery ? (strategy 2 for finding the right target)
phenotypic drug discovery does not rely on the knowledge of the identity of a specific drug target or a hypothesis about its role in disease.
a ‘physiologically relevant’ biological system or cellular signalling pathway is directly interrogated by chemical matter to identify biologically active compounds. This target-agnostic approach is the underlying attribute that differentiates PDD from hypothesis-driven TDD
what is the impact of genomic and genetic tools?
Gene Expression Analysis: Next generation sequencing (NGS) technologies allow the gene expression profile of a biological sample to be detailed on a gene and gene-transcript level. This can be used to compare disease expression profiles for potential new targets where comparative genomics and sequencing can highlight important pathways and potential molecular targets.
There are many databases, suchas ‘The Drug Gene Interaction Database’, based on sequence and structural homology of known drug targets. They offer a wealth of publicly-available genome information to mine and identify the genes for potential therapeutic targets
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Techniques such as CRISPR and RNAi allow modification of selected genes both as a tool for target validation and also the creation of new assay tools.
Why is the understanding of the molecular characteristics of the disease important?
- We have to have confidence that modulating the target will have beneficial effects in our selected disease indication
- We have to understand if the molecular target allows for sufficient modeling and assay development to assess compound efficacy and potency
- Are there sufficient and robust translational models and biomarkers for the assessment of target engagement and efficacy in vivo?
what are elements of the assay cascade?
biochemical assess - binding an pharmacological
cell based models - genetics and pharmacological
in vivo models - PK/PD vs disease models, genetic and pharmacological
High throughput: generating lead molecules and exploring SAR
Low throughput: validation of beneficial biological activity in disease relevant models
