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      Bivalent Ligands for Protein Degradation in Drug Discovery

      review-article
      , , , *
      Computational and Structural Biotechnology Journal
      Research Network of Computational and Structural Biotechnology
      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.

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          Most cited references106

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          Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.

          The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One of the best-characterized enzymes that catalyzes the attachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cullin-F box complex containing Hrt1 (SCF). We sought to artificially target a protein to the SCF complex for ubiquitination and degradation. To this end, we tested methionine aminopeptidase-2 (MetAP-2), which covalently binds the angiogenesis inhibitor ovalicin. A chimeric compound, protein-targeting chimeric molecule 1 (Protac-1), was synthesized to recruit MetAP-2 to SCF. One domain of Protac-1 contains the I kappa B alpha phosphopeptide that is recognized by the F-box protein beta-TRCP, whereas the other domain is composed of ovalicin. We show that MetAP-2 can be tethered to SCF(beta-TRCP), ubiquitinated, and degraded in a Protac-1-dependent manner. In the future, this approach may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.
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            Induced protein degradation: an emerging drug discovery paradigm

            Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function. This article discusses emerging technologies, such as proteolysis-targeting chimaeras (PROTACs), that exploit cellular quality control machinery to selectively degrade target proteins, which could have advantages over traditional approaches, including the potential to target proteins that are not currently therapeutically tractable.
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              Catalytic in vivo protein knockdown by small-molecule PROTACs.

              The current predominant therapeutic paradigm is based on maximizing drug-receptor occupancy to achieve clinical benefit. This strategy, however, generally requires excessive drug concentrations to ensure sufficient occupancy, often leading to adverse side effects. Here, we describe major improvements to the proteolysis targeting chimeras (PROTACs) method, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target's ubiquitination and degradation. These compounds behave catalytically in their ability to induce the ubiquitination of super-stoichiometric quantities of proteins, providing efficacy that is not limited by equilibrium occupancy. We present two PROTACs that are capable of specifically reducing protein levels by >90% at nanomolar concentrations. In addition, mouse studies indicate that they provide broad tissue distribution and knockdown of the targeted protein in tumor xenografts. Together, these data demonstrate a protein knockdown system combining many of the favorable properties of small-molecule agents with the potent protein knockdown of RNAi and CRISPR.
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                Author and article information

                Contributors
                Journal
                Comput Struct Biotechnol J
                Comput Struct Biotechnol J
                Computational and Structural Biotechnology Journal
                Research Network of Computational and Structural Biotechnology
                2001-0370
                25 January 2019
                2019
                25 January 2019
                : 17
                : 160-176
                Affiliations
                Mercachem BV, Kerkenbos 1013, 6546 BB, Nijmegen, the Netherlands
                Author notes
                [* ]Corresponding author. rutger.folmer@ 123456mercachem.com
                Article
                S2001-0370(18)30258-7
                10.1016/j.csbj.2019.01.006
                6369262
                ba7d6d35-3030-4276-936c-66b7331fb0ed
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Categories
                Review Article

                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

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