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Knockouts model the 100 best-selling drugs—will they model the next 100?

Key Points

  • The Target Base and New Target Innovation in the Pharmaceutical Industry

  • This section describes the small number of targets that form the basis of the economics of the industry and how rare and valuable completely new targets are, both economically and for the treatment of unmet medical needs.

  • Genetics Works

  • This section summarizes the data from the knockout of the targets of the top 100 selling drugs of the year 2001.

  • Going Forward With Reverse Genetics

  • This section describes the prospective use of mouse knockout information to define the next targets for drug development.

  • Knocking Out the Druggable Genome

  • This section summarizes our efforts to knock out all druggable genes in order to discover new drug targets and estimates are made for the number of high quality targets the genome may contain.

Abstract

The biopharmaceutical industry is currently faced with a tremendous number of potential drug targets identified through the sequencing of the human genome. The challenge ahead is to delineate those targets with the greatest value for therapeutic intervention. Here, we critically evaluate mouse-knockout technology for target discovery and validation. A retrospective evaluation of the knockout phenotypes for the targets of the 100 best-selling drugs indicates that these phenotypes correlate well with known drug efficacy, illuminating a productive path forward for discovering future drug targets. Prospective mining of the druggable genome is being catalysed by large-scale mouse knockout programs combined with phenotypic screens focused on identifying targets that modulate mammalian physiology in a therapeutically relevant manner.

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Figure 1: Worldwide biopharmaceutical productivity: new molecular entities versus breakthrough or innovator targets.
Figure 2: Knocking out the druggable genome: The Genome5000 Program.
Figure 3: Comprehensive phenotypic screen for drug targets.

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Correspondence to Brian P. Zambrowicz.

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DATABASES

Cancer.Gov

Breast cancer

chronic myeloid leukemia

prostate cancer

Online Mendelian Inheritance in Man

Adenomatous polyposis of the colon

osteoporosis

FURTHER INFORMATION

Encyclopedia of Life Sciences

Mouse knockouts

Glossary

CHRONIC MYELOID LEUKAEMIA

A leukaemia characterized by the presence of large numbers of abnormal mature granulocytes circulating in the blood.

METABOLOMICS

The quantitative measurement of all low-molecular-weight metabolites in an organism's cells at a specified time under specific environmental conditions.

GASTROESOPHAGEAL REFLUX DISEASE

A disorder in which there is recurrent return of stomach contents back up into the oesophagus, frequently causing heartburn, a symptom of irritation of the oesophagus by stomach acid.

ERYTHROPOIESIS

Red blood cell development, in which a pluripotent stem cell produces, by a series of divisions, committed stem cells that give rise to cells that will divide only a few more times to produce mature erythrocytes.

NEUTROPENIA

A decrease in neutrophil numbers in the peripheral blood.

DECIDUALIZATION

Formation of the deciduas, the inner layer of the wall of the uterus, which envelops the embryo, forms a part of the placenta and is discharged with it.

CARRAGEENAN

A sulphated cell-wall polysaccharide found in certain red algae, which contains repeating sulphated disaccharides of galactose, and sometimes anhydrogalactose, and is used to induce an inflammatory lesion when injected into experimental animals.

TOPOISOMERASE

Enzymes that change the degree of supercoiling in DNA by cutting one or both strands.

WERNER'S SYNDROME

A disorder causing accelerated aging consisting of scleroderma-like skin changes, bilateral juvenile cataracts, progeria, hypogonadism, and diabetes mellitus; it results from the autosomal recessive inheritance of a mutation in a topoisomerase gene.

ORTHOLOGOUS GENE

Homologous gene in different species, the lineage of which derives from a common ancestral gene without gene duplication or horizontal transmission.

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Zambrowicz, B., Sands, A. Knockouts model the 100 best-selling drugs—will they model the next 100?. Nat Rev Drug Discov 2, 38–51 (2003). https://doi.org/10.1038/nrd987

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