Knockouts model the 100 best-selling drugs - Will they model the next 100?

被引：301

作者：

Zambrowicz, BP ^{[1
]}

Sands, AT ^{[1
]}

机构：

[1] Lexicon Genet Inc, The Woodlands, TX 77381 USA

来源：

NATURE REVIEWS DRUG DISCOVERY | 2003年 / 2卷 / 01期

关键词：

D O I：

10.1038/nrd987

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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.

引用

收藏

页码：38 / 51

页数：14

相关论文

共 113 条

[1] Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2 [J].

Abu-Elheiga, L ;

Matzuk, MM ;

Abo-Hashema, KAH ;

Wakil, SJ .

SCIENCE, 2001, 291 (5513) :2613-2616

[2] Full-speed mammalian genetics:: in vivo target validation in the drug discovery process [J].

Abuin, A ;

Holt, KH ;

Platt, KA ;

Sands, AT ;

Zambrowicz, BP .

TRENDS IN BIOTECHNOLOGY, 2002, 20 (01) :36-42

[3] Early neonatal death in mice homozygous for a null allele of the insulin receptor gene [J].

Accili, D ;

Drago, J ;

Lee, EJ ;

Johnson, MD ;

Cool, MH ;

Salvatore, P ;

Asico, LD ;

Jose, PA ;

Taylor, SI ;

Westphal, H .

NATURE GENETICS, 1996, 12 (01) :106-109

[4] Insight into prostaglandin, leukotriene, and other eicosanoid functions using mice with targeted gene disruptions [J].

Austin, SC ;

Funk, CD .

PROSTAGLANDINS & OTHER LIPID MEDIATORS, 1999, 58 (5-6) :231-252

[5] Nociception in cyclooxygenase isozyme-deficient mice [J].

Ballou, LR ;

Botting, RM ;

Goorha, S ;

Zhang, JY ;

Vane, JR .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (18) :10272-10276

[6] Augmentation of antigen receptor-mediated responses by histamine H1 receptor signaling [J].

Banu, Y ;

Watanabe, T .

JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 189 (04) :673-682

[7] Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase [J].

Bergstrom, JD ;

Bostedor, RG ;

Masarachia, PJ ;

Reszka, AA ;

Rodan, G .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2000, 373 (01) :231-241

[8] Defective T cell development and function in calcineurin Aβ-deficient mice [J].

Bueno, OF ;

Brandt, EB ;

Rothenberg, ME ;

Molkentin, JD .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (14) :9398-9403

[9] Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass [J].

Chen, AS ;

Marsh, DJ ;

Trumbauer, ME ;

Frazier, EG ;

Guan, XM ;

Yu, H ;

Rosenblum, CI ;

Vongs, A ;

Feng, Y ;

Cao, LH ;

Metzger, JM ;

Strack, AM ;

Camacho, RE ;

Mellin, TN ;

Nunes, CN ;

Min, W ;

Fisher, J ;

Gopal-Truter, S ;

MacIntyre, DE ;

Chen, HY ;

Van der Ploeg, LHT .

NATURE GENETICS, 2000, 26 (01) :97-102

[10] ROLE OF LEUKOTRIENES REVEALED BY TARGETED DISRUPTION OF THE 5-LIPOXYGENASE GENE [J].

CHEN, XS ;

SHELLER, JR ;

JOHNSON, EN ;

FUNK, CD .

NATURE, 1994, 372 (6502) :179-182

← 1 2 3 4 5 6 7 8 9 10 →