Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes

被引：127

作者：

Schreiber, Stuart L. ^{[1
,2
,3
,4
]}

Kotz, Joanne D. ^{[1
,4
]}

Li, Min ^{[7
]}

Aube, Jeffrey ^{[8
,9
]}

Austin, Christopher P. ^{[10
,11
]}

Reed, John C. ^{[12
,13
]}

Rosen, Hugh ^{[14
,15
,16
]}

White, E. Lucile ^{[19
]}

Sklar, Larry A. ^{[20
,21
]}

Lindsley, Craig W. ^{[23
,24
]}

Alexander, Benjamin R. ^{[1
,6
]}

Bittker, Joshua A. ^{[1
,5
]}

Clemons, Paul A. ^{[1
,4
]}

De Souza, Andrea ^{[1
]}

Foley, Michael A. ^{[1
]}

Palmer, Michelle ^{[1
]}

Shamji, Alykhan F. ^{[1
,4
]}

Wawer, Mathias J. ^{[1
,4
]}

McManus, Owen ^{[7
]}

Wu, Meng ^{[7
]}

Zou, Beiyan ^{[7
]}

Yu, Haibo ^{[7
]}

Golden, Jennifer E. ^{[8
]}

Schoenen, Frank J. ^{[8
]}

Simeonov, Anton ^{[10
,11
]}

Jadhav, Ajit ^{[10
,11
]}

Jackson, Michael R. ^{[12
,13
]}

Pinkerton, Anthony B. ^{[12
,13
]}

Chung, Thomas D. Y. ^{[12
,13
]}

Griffin, Patrick R. ^{[14
,15
,17
]}

Cravatt, Benjamin F. ^{[14
,15
,16
]}

Hodder, Peter S. ^{[14
,15
]}

Roush, William R. ^{[14
,15
,18
]}

Roberts, Edward ^{[14
,15
]}

Chung, Dong-Hoon ^{[19
]}

Jonsson, Colleen B. ^{[19
]}

Noah, James W. ^{[19
]}

Severson, William E. ^{[19
]}

Ananthan, Subramaniam ^{[19
]}

Edwards, Bruce ^{[20
,21
]}

Oprea, Tudor I. ^{[20
,22
]}

Conn, P. Jeffrey ^{[23
,24
]}

Hopkins, Corey R. ^{[23
,24
]}

Wood, Michael R. ^{[23
,24
]}

Stauffer, Shaun R. ^{[23
]}

Emmitte, Kyle A. ^{[23
,24
]}

机构：

[1] Broad Inst Harvard & MIT, Probe Dev Ctr, Cambridge, MA 02142 USA

[2] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA

[3] Broad Inst Harvard & MIT, Howard Hughes Med Inst, Cambridge, MA 02142 USA

[4] Broad Inst Harvard & MIT, Ctr Sci Therapeut, Cambridge, MA 02142 USA

[5] Broad Inst Harvard & MIT, Ctr Dev Therapeut, Cambridge, MA 02142 USA

[6] Broad Inst Harvard & MIT, Med & Populat Genet, Cambridge, MA 02142 USA

[7] Johns Hopkins Sch Med, Ion Channel Ctr, Baltimore, MD 21205 USA

[8] Univ Kansas, Specialized Chem Ctr, Lawrence, KS 66045 USA

[9] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA

[10] NIH, NIH Chem Genom Ctr, Rockville, MD 20850 USA

[11] Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA

[12] Sanford Burnham Med Res Inst, Conrad Prebys Ctr Chem Genom, La Jolla, CA 92037 USA

[13] Sanford Burnham Med Res Inst, Conrad Prebys Ctr Chem Genom, Lake Nona, FL 32827 USA

[14] Scripps Res Inst, Mol Screening Ctr, La Jolla, CA 92037 USA

[15] Scripps Res Inst, Mol Screening Ctr, Jupiter, FL 33458 USA

[16] Scripps Res Inst, Dept Chem Physiol, La Jolla, CA 92037 USA

[17] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA

[18] Scripps Res Inst, Dept Chem, Jupiter, FL 33458 USA

[19] So Res Inst, Southern Res Specialized Biocontainment Screening, Birmingham, AL 35205 USA

[20] Univ New Mexico, Ctr Mol Discovery, Albuquerque, NM 87131 USA

[21] Univ New Mexico, Sch Med, Dept Pathol, Albuquerque, NM 87131 USA

[22] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA

[23] Vanderbilt Univ, Med Ctr, Vanderbilt Specialized Chem Ctr Accelerated Probe, Nashville, TN 37232 USA

[24] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

来源：

CELL | 2015年 / 161卷 / 06期

关键词：

PYRUVATE-KINASE; PPAR-GAMMA; GAUCHER-DISEASE; DRUG DISCOVERY; ALLOSTERIC MODULATORS; SELECTIVE INHIBITORS; ALZHEIMERS-DISEASE; S1P(4)-R AGONISTS; TARGET ENGAGEMENT; FLUID RETENTION;

D O I：

10.1016/j.cell.2015.05.023

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the NIH launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines but also highlight the need to innovate the science of therapeutic discovery.

引用

页码：1252 / 1265

页数：14

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