From the Guidelines
Target activation is a crucial process in drug discovery that involves the technical evaluation of whether a target has a key role in a disease process and whether pharmacological modulation of the target could be effective in a defined patient population. According to the GOT-IT recommendations, published in Nature Reviews Drug Discovery in 2021 1, target activation is an essential step in the development of new therapies, and its validation is critical to reduce attrition in phase II clinical trials and lower the cost of developing new molecular entities.
The process of target activation involves various strategies to provide validation of the target, including the identification of a new drug target, such as an enzyme linked to a disease process, and the use of guiding questions to stimulate academic scientists' awareness of factors that make translational research more robust and efficient 1. The GOT-IT framework is intended to facilitate academia–industry collaboration and support academic scientists and funders of translational research in identifying and prioritizing target assessment activities.
Key aspects of target activation include:
- Target validation: the technical evaluation of whether a target has a key role in a disease process and whether pharmacological modulation of the target could be effective in a defined patient population
- Druggability: the potential of a target to be modulated by a drug
- Target-related safety issues: the potential risks associated with targeting a specific protein or pathway
- Biomarker research: the identification of biomarkers that can be used to monitor the effectiveness of a treatment
The most effective approach to target activation is to use a combination of pharmacological and physiological methods, taking into account the body's natural circadian rhythms and the variable expression of cellular receptors throughout the day. This approach can enhance efficacy while potentially reducing side effects, and can be achieved by administering medications when their target receptors are most abundant or responsive, and combining pharmacological approaches with lifestyle modifications like timed exercise or specific dietary patterns.
From the Research
Definition of Target Activation
- Target activation refers to the process of activating a specific target, such as a gene or a cell, to achieve a desired outcome.
- In the context of gene editing, target activation can be achieved through the use of CRISPR/Cas9 system, which allows for the regulation of endogenous gene expression without creating DNA double-strand breaks 2.
- Target activation can also refer to the activation of specific cells, such as T cells, which can be achieved through the use of bispecific antibodies or chimeric antigen receptors 3, 4.
Mechanisms of Target Activation
- The CRISPR/Cas9 system can be used to activate target genes by recruiting Cas9 and transcriptional activation complexes to target loci through modified single guide RNAs 2.
- Bispecific antibodies can activate T cells by binding to specific antigens on the surface of target cells, leading to the activation of T cells and the release of cytokines 3.
- Chimeric antigen receptors can also activate T cells by recognizing specific antigens on the surface of target cells, leading to the activation of T cells and the release of cytokines 4.
Applications of Target Activation
- Target activation has potential applications in the treatment of various diseases, including cancer, diabetes, muscular dystrophy, and acute kidney disease 2.
- Target activation can also be used to prevent unwanted off-target T cell activation, which can lead to severe side effects such as cytokine release syndrome 3.
- The use of target activation in the treatment of neurodegenerative diseases, such as Alzheimer's disease, is also being explored, with the goal of preventing neuronal toxicity and promoting neuroprotection 5.