Target Identification and Drug Development ppt

Target Identification in Drug Development

Introduction

  • Definition of a target: A biological entity implicated in a disease context, encompassing elements such as genes, proteins, or RNA sections.

  • The importance of target identification in drug development, particularly for novel therapeutics aimed at diseases with high unmet medical needs.

Scenario Exercise

  • Situation: A new employee at a medical device company, Image X, is tasked with developing a portable diagnostic tool for malaria.

    • Goals:

    • Create a sensitive, user-friendly diagnostic machine for field use, outpacing competitors.

    • Conduct a group discussion to identify critical points in malaria diagnosis, assess knowledge gaps, and propose solutions.

Problem Identification

  • The overarching question: "Can we eradicate malaria?"

Understanding Drug Targets

Definition of a Target

  • A target can be a gene, protein, or any biological molecule relevant to disease pathology.

  • Necessary characteristics of a good target include:

    • Efficacy and Safety: The target should induce a desired biological response without causing harm.

    • Druggability: This means the target is accessible and can bind to drug molecules effectively.

Drug Discovery Context

  • Many biological targets are identified through ongoing experimental, mechanistic, and pharmacological studies.

  • A theoretical evaluation of molecular druggability is essential, alongside potential side effects and commercial viability considerations.

    • Reference to a study from Drug Discovery Today indicates the historic limitations of druggable molecules despite advancements with biologicals.

Characteristics of Drug Targets

Properties of an Ideal Drug Target

  • A target must influence disease pathology and have a role in modifying disease progression.

  • Modulation of the target: It should be less critical under normal physiological conditions or in other diseases.

  • For targets where druggability is not evident (e.g., certain kinases), a 3D-structure must be accessible.

  • It's imperative that the target can undergo high-throughput screening (assayability).

  • Expression Distribution: A good target should not be uniformly expressed throughout the body, enhancing therapeutic specificity.

  • Biomarkers: The existence of disease-specific biomarkers to monitor treatment efficacy is essential.

  • Safety Predictions: Favorable expectations regarding potential side effects based on available phenotype data (such as knockout (k.o.) mice studies or genetic mutation databases).

  • Intellectual Property (IP) considerations are pivotal: freedom to operate and lack of competition on the target.

Properties Recap

  1. Disease-modifying nature

  2. Less vital modulation under normal conditions

  3. Available 3D structure for complex targets

  4. High assayability for screening

  5. Uneven tissue expression

  6. Specific biomarkers for efficacy

  7. Favorable safety profile predictions

  8. Strong IP position

Target Identification Methods

Resources for Target Identification

  • DrugBank Database: A crucial resource for information on drugs and their targets.

  • Literature: Identifying potential targets through ongoing research and studies on gene functions.

  • RNA/Protein Expression Studies: Descriptive studies comparing diseased versus healthy tissues can give initial hints at target potential.

  • Pathway Analyses: Integrative data analysis tools (like STRING) can provide insights into regulatory mechanisms that may be targeted.

  • Proteomics: Investigating differential enzymatic activity in diseased versus normal tissues can reveal target candidates.

  • Genetic Studies: Alterations, somatic mutations, gene fusion, and copy number variations are significant, especially in oncology.

Factors Leading to Successful Target Identification

  • Deep understanding of the disease and its molecular mechanisms.

  • Availability of predictive models and technologies to support target identification.

  • Example: The interleukin-2-inducible tyrosine kinase (Itk) as a therapeutic target in inflammatory skin diseases, substantiated through knockout models and SMOL inhibitors.

Drug Target Assessment Phases

Molecular Target Assessment

  • Characterization of molecular mechanisms via ex vivo and in vitro studies, utilizing techniques like siRNA.

  • Evaluation of disease modulation through target engagement in relevant in vivo models (e.g., using k.o. mice).

Drugability Assessment Process

  • Queries guiding assessment:

    • Availability of SMOL binding domains or extracellular domains for biologics.

    • Existence of a crystal structure.

    • Capability for high-throughput assays.

    • Identification of target-specific biomarkers.

    • Evaluation of potential adverse effects.

    • Consideration of IP situation, including freedom to operate and competition.

    • Tissue specificity in expression and feasibility of commercialization.

Clinical Relevance and Safety Considerations

Critical Path Questions for Targets

  • Questions regarding the therapeutic relevance of target manipulation and the safety of interventions, focusing on potential adverse events and human relevance.

  • The focus is on ensuring that any therapeutic manipulation is not only effective but safe and transferable for human use.

Conclusion

  • The effective identification and characterization of drug targets are essential for developing new treatments, particularly for diseases with substantial unmet medical needs like malaria. Integration of biological, pharmacological, and commercial factors is necessary for advancing from target identification to successful drug development.