The definition of "target" itself is something debated within the pharmaceutical
industry, however, the distinction between a new and an established target can be
made without a full understanding of just how a target is defined. This distinction is
typically made by pharmaceutical companies engaged in discovery and development
of small molecule therapeutics.
Established targets are those targets for which there is a good scientific
understanding, supported by a lengthy publication history, of both how the target
functions in normal physiology and how it is involved in human pathology. Established targets relate directly to the amount of background information available on a target, in particular functional information.
In general, new targets are all those targets that are not "established targets" but
which have been or are presently the subject of drug discovery campaigns. These
typically include newly discovered proteins, or proteins whose function has been
revealed as a result of basic scientific research.
The focus in the second stage is to identify a chemical or series of chemicals that will
interact with the target and have the potential to impact the disease studied. After
screening many compounds, researchers focus on whether or not the molecule binds
to a target protein.
- Attempt to confirm a target
- Attempt to determine DNA and protein sequence
- Attempt to elucidate structure and function of
- Prove therapeutic concept in animals
- Develop assay for high-throughput
- Mass screening and/or directed
- Select one or more lead structures
Every year pharmaceutical companies identify tens or hundreds of thousands of
compounds that may be useful new drugs. The process of finding a new
drug that affects a chosen target for a particular disease usually involves high-throughput
screening (HTS), in which large libraries of chemicals are tested for their
ability to modify the target. This process enables researchers to conduct millions of biochemical, genetic or pharmacological tests and rapidly identify those that modulate a particular biomolecular pathway.
These screening tests are usually simple binding assays (asking does the molecule
bind to a target protein?). Testing is done in two stages: chemical similarity is
important in both these stages
- Lead Identification (find a compound that binds to the target)
- Lead Optimization (find a compound that binds better)
When a "lead" has been identified, the next stage is to find compounds that are
similar to it, that might bind even better (optimization). This can involve 'similarity
searching' to find compounds previously made, or available commercially for
purchase. To assess similarities, the following properties are analyzed: absorption, distribution, metabolism, excretion, toxicity (ADMET).
In later stages, medicinal chemists make specific changes to the lead compound,
which they hope will improve its binding affinity. When testing a large number of
compounds in order to identify a new "lead", it is best to have compounds that are as
different from each other as possible.
Pharmaceutical companies purchase large numbers of compounds from third-party
suppliers. They also synthesize combinatorial "libraries" of compounds. Chemical
"diversity" is an important feature of such compound collections and libraries hoping
to cover as much "chemical space" as possible.
Candidate Drug Nomination
The third stage of drug development is used to identify a candidate drug that meets
most criteria and passes additional evaluations including safety assessment,
pharmaceutical pre-formulation and process chemistry studies.
Fundamental Questions in Cancer Drug Development
1. Is this the right target?
Is the biological process targeted directly implicated in the development and
progression of the disease?
2. Is this the right drug?
Does the new drug hit the target with sufficient potency to affect the underlying
biology? Can this be measured in the laboratory and also in humans with the
3. What is the right dose and schedule?
Can an optimal biological effect dose and schedule be defined based on the
measurement of the target either directly or indirectly?
4. What is/are the right tumor(s)?
Has the new drug been tested in the right setting? What is the rationale for
choosing a particular tumor as a target?
5. Issues in the development of Phase III clinical trials launch phase:
- Phase III trials often require thousands of patients as participants
- How to choose the appropriate drug to compare the new one too
- Different treatment paradigms in different parts of the world
- Choosing the appropriate endpoint
- Clinical trials may take years to complete due to the choice of long term
endpoints such as survival
- The 'comparator' drug chosen may no longer be relevant by the time the trial is
completed due to a rapidly changing environment.
6. Criteria for determining clinical benefit in oncology patients:
- Should have direct effects on the disease
- Overall survival is the most important, but there are also others such as:
- Objective response rate (disease shrinks or disappears after treatment)
- Duration of response
- Time to progression
- Disease-free survival
- Should have effects on other clinical consequences of disease or treatment
- Reduction in symptoms (e.g. pain, anorexia)
- Reduction of treatment toxicities (e.g. nausea, vomiting, diarrhea, mucositis,
- List of problems with many current drugs on the market:
- Poor biopharmaceutical properties
- Lack of efficacy - 29%
- Toxicity - 21%
- Market reasons - 6%
- Other - 5%
The success rate of developing new drugs needs to be improved. The chart below
shows some of the new technologies that may enable this to happen.
||High dose, intermittent
||Low dose, chronic
||Same, with biomarker
New biological Information
Pharmacogenomics - the branch of pharmacology which focuses on the influence of genetic variation on drug response in patients - offers great potential for identification of new targets for
- Genomic profiling of individual diseases will help identify many potential
Genomic profiling of individual diseases will help identify subgroups of patients that will benefit from a targeted therapy and others that may not - responders and non-responders.