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Bivalent Ligands for Protein Degradation in Drug Discovery
review-article
25 January 2019
PROTAC,
Protein degradation,
Degrader,
Proteasome,
Chimera,
Bivalent ligand,
ABCB1, ATP-binding cassette sub-family B member 1,
AD, Alzheimer's disease,
AHR, aryl hydrogen receptor,
ALK, anaplastic lymphoma kinase,
Aβ, amyloid-β,
Bcl6, B-cell lymphoma 6,
BET, bromodomain and extra-terminal,
Brd4, bromodomain 4,
BTK, Bruton's tyrosine kinase,
CDK9, cyclin dependent kinase 9,
cIAP1, cellular inhibitor of apoptosis protein,
CK2, Casein kinase 2,
CLIPTAC, click-formed proteolysis targeting chimera,
CRBN, Cereblon,
DC50, the compound concentration that results in 50% target protein degradation,
DHODH, Dihydroorotate dehydrogenase,
ERK1, extracellular signal-regulated kinase 1,
ERRα, estrogen-related receptor alpha,
ERα, estrogen receptor alpha,
EZH2, enhancer of zeste homolog 2,
FLT3, FMS-like tyrosine kinase-3,
FRS2, fibroblast growth factor receptor substrate 2,
GCN5, general control nonderepressible 5,
GPCR, G-protein coupled receptor,
GST, glutathione S-transferase,
HDAC, histone deacetylase,
HTS, high-throughput screening,
MDM2, mouse double-minute 2 homolog,
MetAP-2, methionine aminopeptidase-2,
PCAF, P300/CBP-associated factor,
PEG, polyethylene glycol,
PI3K, phosphatidylinositol-3-kinase,
PLK-1, polo-like kinase 1,
POI, protein of interest,
PROTAC, proteolysis targeting chimeras,
RAR, retinoic acid receptor,
RIPK2, receptor-interacting serine/threonine-protein kinase 2,
RTK, receptor tyrosine kinase,
SARM, selective androgen receptor modulator,
SNIPER, specific and non-genetic IAP-dependent protein eraser,
TBK1, TANK-Binding kinase 1,
TRIM24, tripartite motif-containing 24 (also known as TIF1α),
VHL, Von Hippel-Lindau
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Abstract
Targeting the “undruggable” proteome remains one of the big challenges in drug discovery. Recent innovations in the field of targeted protein degradation and manipulation of the ubiquitin-proteasome system open up new therapeutic approaches for disorders that cannot be targeted with conventional inhibitor paradigms. Proteolysis targeting chimeras (PROTACs) are bivalent ligands in which a compound that binds to the protein target of interest is connected to a second molecule that binds an E3 ligase via a linker. The E3 protein is usually either Cereblon or Von Hippel-Lindau. Several examples of selective PROTAC molecules with potent effect in cells and in vivo models have been reported. The degradation of specific proteins via these bivalent molecules is already allowing for the study of biochemical pathways and cell biology with more specificity than was possible with inhibitor compounds. In this review, we provide a comprehensive overview of recent developments in the field of small molecule mediated protein degradation, including transcription factors, kinases and nuclear receptors. We discuss the potential benefits of protein degradation over inhibition as well as the challenges that need to be overcome.
Graphical Abstract
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Most cited references106
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- Abstract: found
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Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.
K M Sakamoto, K. -B. Kim, A Kumagai … (2001)
- Record: found
- Abstract: found
- Article: not found
Induced protein degradation: an emerging drug discovery paradigm
Ashton C Lai, Craig M Crews (2016)
- Record: found
- Abstract: found
- Article: not found
Catalytic in vivo protein knockdown by small-molecule PROTACs.
Daniel Bondeson, Alina Mares, Ian E D Smith … (2015)
Author and article information
protac,protein degradation,degrader,proteasome,chimera,bivalent ligand,abcb1, atp-binding cassette sub-family b member 1,ad, alzheimer's disease,ahr, aryl hydrogen receptor,alk, anaplastic lymphoma kinase,aβ, amyloid-β,bcl6, b-cell lymphoma 6,bet, bromodomain and extra-terminal,brd4, bromodomain 4,btk, bruton's tyrosine kinase,cdk9, cyclin dependent kinase 9,ciap1, cellular inhibitor of apoptosis protein,ck2, casein kinase 2,cliptac, click-formed proteolysis targeting chimera,crbn, cereblon,dc50, the compound concentration that results in 50% target protein degradation,dhodh, dihydroorotate dehydrogenase,erk1, extracellular signal-regulated kinase 1,errα, estrogen-related receptor alpha,erα, estrogen receptor alpha,ezh2, enhancer of zeste homolog 2,flt3, fms-like tyrosine kinase-3,frs2, fibroblast growth factor receptor substrate 2,gcn5, general control nonderepressible 5,gpcr, g-protein coupled receptor,gst, glutathione s-transferase,hdac, histone deacetylase,hts, high-throughput screening,mdm2, mouse double-minute 2 homolog,metap-2, methionine aminopeptidase-2,pcaf, p300/cbp-associated factor,peg, polyethylene glycol,pi3k, phosphatidylinositol-3-kinase,plk-1, polo-like kinase 1,poi, protein of interest,protac, proteolysis targeting chimeras,rar, retinoic acid receptor,ripk2, receptor-interacting serine/threonine-protein kinase 2,rtk, receptor tyrosine kinase,sarm, selective androgen receptor modulator,sniper, specific and non-genetic iap-dependent protein eraser,tbk1, tank-binding kinase 1,trim24, tripartite motif-containing 24 (also known as tif1α),vhl, von hippel-lindau
protac, protein degradation, degrader, proteasome, chimera, bivalent ligand, abcb1, atp-binding cassette sub-family b member 1, ad, alzheimer's disease, ahr, aryl hydrogen receptor, alk, anaplastic lymphoma kinase, aβ, amyloid-β, bcl6, b-cell lymphoma 6, bet, bromodomain and extra-terminal, brd4, bromodomain 4, btk, bruton's tyrosine kinase, cdk9, cyclin dependent kinase 9, ciap1, cellular inhibitor of apoptosis protein, ck2, casein kinase 2, cliptac, click-formed proteolysis targeting chimera, crbn, cereblon, dc50, the compound concentration that results in 50% target protein degradation, dhodh, dihydroorotate dehydrogenase, erk1, extracellular signal-regulated kinase 1, errα, estrogen-related receptor alpha, erα, estrogen receptor alpha, ezh2, enhancer of zeste homolog 2, flt3, fms-like tyrosine kinase-3, frs2, fibroblast growth factor receptor substrate 2, gcn5, general control nonderepressible 5, gpcr, g-protein coupled receptor, gst, glutathione s-transferase, hdac, histone deacetylase, hts, high-throughput screening, mdm2, mouse double-minute 2 homolog, metap-2, methionine aminopeptidase-2, pcaf, p300/cbp-associated factor, peg, polyethylene glycol, pi3k, phosphatidylinositol-3-kinase, plk-1, polo-like kinase 1, poi, protein of interest, protac, proteolysis targeting chimeras, rar, retinoic acid receptor, ripk2, receptor-interacting serine/threonine-protein kinase 2, rtk, receptor tyrosine kinase, sarm, selective androgen receptor modulator, sniper, specific and non-genetic iap-dependent protein eraser, tbk1, tank-binding kinase 1, trim24, tripartite motif-containing 24 (also known as tif1α), vhl, von hippel-lindau