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Comput Struct Biotechnol J. 2019 Jan 25;17:160-176. doi: 10.1016/j.csbj.2019.01.006. eCollection 2019.

Bivalent Ligands for Protein Degradation in Drug Discovery.

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Mercachem BV, Kerkenbos 1013, 6546 BB, Nijmegen, the Netherlands.


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.


ABCB1, ATP-binding cassette sub-family B member 1; AD, Alzheimer's disease; AHR, aryl hydrogen receptor; ALK, anaplastic lymphoma kinase; Aβ, amyloid-β; BET, bromodomain and extra-terminal; BTK, Bruton's tyrosine kinase; Bcl6, B-cell lymphoma 6; Bivalent ligand; Brd4, bromodomain 4; CDK9, cyclin dependent kinase 9; CK2, Casein kinase 2; CLIPTAC, click-formed proteolysis targeting chimera; CRBN, Cereblon; Chimera; DC50, the compound concentration that results in 50% target protein degradation; DHODH, Dihydroorotate dehydrogenase; Degrader; 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; PROTAC, proteolysis targeting chimeras; Proteasome; Protein degradation; 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; cIAP1, cellular inhibitor of apoptosis protein

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