Elsevier

Drug Discovery Today

Volume 10, Issue 2, 15 January 2005, Pages 139-147
Drug Discovery Today

Review
Target-based drug discovery: is something wrong?

https://doi.org/10.1016/S1359-6446(04)03316-1Get rights and content

Abstract

For the past decade the pharmaceutical industry has experienced a steady decline in productivity and a striking observation is that the decline coincided with the introduction of target-based drug discovery. The target-based approach can very effectively develop novel treatments for a validated target, but the process of target validation is complex and associated with a high degree of uncertainty. The purpose of this paper is to analyse these aspects in detail to determine if weaknesses in this part of the drug discovery path might explain why this paradigm has not resulted in increased productivity over the traditional in vivo approach, considering its superiority in screening capacity and its ability to define rational drug discovery programs.

Section snippets

Target-based drug discovery

A target is usually a single gene, gene product or molecular mechanism that has been identified on the basis of genetic analysis or biological observations [9, 10, 11, 12, 13, 14]. The literature does not distinguish between target classes, but for the present analysis they will be divided into two classes: genetic or mechanistic targets. Genetic targets represent genes or gene products that, in specific diseases, have been found to carry mutations (e.g. the familial forms of Alzheimer's

Managing uncertainty

Methods for determining a strategy in a complex environment have received considerable attention in the management literature, but they can, in general, be divided into two approaches. One approach [29] recommends first gathering all relevant information, followed by analysis of every possible outcome of every possible decision. On the basis of this complete picture, one can then choose the optimal strategy, plan it in detail and stick to the plan until it has been implemented. This is, of

An integrated target/physiology-based drug discovery paradigm

The optimal approach to drug discovery necessarily depends upon the specific company and its strategy, but a proposal for an approach that integrates the above issues is shown in FIGURE 3, FIGURE 4. The first step is to classify the target according to the criteria in Table 1. Next, to conduct a comprehensive strategy determination that includes collecting information regarding the indication and the biology of the target; setting a clear strategy for proof-of-principle studies and determining

Conclusions

The introduction raised the question whether the shift to target-based drug discovery could be responsible for the decline in the productivity of the pharmaceutical industry. It is not the only explanation, because many factors have changed over the past 10 years [1, 2, 3, 4, 5, 6, 7, 8, 9, 10], but during this period it has been the dominating paradigm and we have seen a strong decline in the number of new molecules entering clinical testing, suggesting that it could be a contributing factor.

Acknowledgements

I thank Professor D Hinzen and Jeanette Sams-Dodd for commenting on the manuscript.

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