Drug Discovery → Hit-to-Lead Techniques

Hit-to-Lead Techniques

Now that we understand the two approaches taken to discovery of new drugs and we know what molecules are being studied we will learn about the different techniques that can push forward hits into lead territory. Leads are sufficiently potent, selective, and have favorable PK to pre-clinically assess the validity of the therapeutic hypothesis in an animal model. Usually a primary assay is used for hit discovery and a secondary orthogonal assay is used for hit validation. An orthogonal readout is desired to lessen the chances of a false positive.

1. In vitro and cell-based assays
   1. In-vitro assays monitor a surrogate readout like
      1. Catalytic action of an isolated enzyme
      2. Binding of an antibody to a defined antigen
      3. Growth of an engineered cell line
   2. These assays can range in complexity from simple cytotoxicity assays or cell growth to reporter gene assays that monitor activation or upregulation of certain genes or their gene products
   3. Usually more robust and cost-effective and have fewer ethical implications than whole-animal experiments
2. In vivo, animal models
   1. Animal models are developed to have specific characteristic that mimic human diseases
      1. Transgenic animals: deleted/added/modulated genes
   2. Used to assess both the pharmacology and biological efficacy in parallel but are usually more complex and require more regulation
   3. The lack of animal models (or inadequate models) is a major hurdle in drug discovery
   4. Allows tolerability to be explored