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The rise of fragment-based drug discovery


The search for new drugs is plagued by high attrition rates at all stages in research and development. Chemists have an opportunity to tackle this problem because attrition can be traced back, in part, to the quality of the chemical leads. Fragment-based drug discovery (FBDD) is a new approach, increasingly used in the pharmaceutical industry, for reducing attrition and providing leads for previously intractable biological targets. FBDD identifies low-molecular-weight ligands (150 Da) that bind to biologically important macromolecules. The three-dimensional experimental binding mode of these fragments is determined using X-ray crystallography or NMR spectroscopy, and is used to facilitate their optimization into potent molecules with drug-like properties. Compared with high-throughput-screening, the fragment approach requires fewer compounds to be screened, and, despite the lower initial potency of the screening hits, offers more efficient and fruitful optimization campaigns. Here, we review the rise of FBDD, including its application to discovering clinical candidates against targets for which other chemistry approaches have struggled.

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Figure 1: The discovery of AT7519, an inhibitor of cyclin dependent kinases (CDK) 1 and 2.
Figure 2: The discovery of ABT-263, an inhibitor of protein-protein interactions involving Bcl-2 family proteins.


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We acknowledge all Astex scientists past and present and Harren Jhoti and Chris Abell for helpful comments on the manuscript.

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Correspondence to David C. Rees.

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Competing interests

The authors are employees of Astex Therapeutics, a drug discovery company that uses fragment-based drug discovery.

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Murray, C., Rees, D. The rise of fragment-based drug discovery. Nature Chem 1, 187–192 (2009).

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