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Order](https://www.sigmaaldrich.com/US/en/quick-order) Cart0 [Home](https://www.sigmaaldrich.com/US/en)[Targeted Protein Degradation](https://www.sigmaaldrich.com/US/en/applications/chemistry-and-synthesis/protein-degradation)Degrader Building Blocks for Targeted Protein Degradation # Degrader Building Blocks for Targeted Protein Degradation __Section Overview__ - [Targeted Protein Degradation](https://www.sigmaaldrich.com#target-protein-degradation) - [Challenges for Protein Degrader Synthesis](https://www.sigmaaldrich.com#challenges-for-protein-degrader-synthesis) - [Streamlined Synthesis of Heterobifunctional Degrader Libraries](https://www.sigmaaldrich.com#synthesis-of-heterobifunctional) - [Diversity of the Ligand - Linker Conjugates](https://www.sigmaaldrich.com#diversity-of-ligand) - [Advantages](https://www.sigmaaldrich.com#advantages) - [Let Us Help You Build Your Degrader Library Based on What Is Most Important to You](https://www.sigmaaldrich.com#build-your-degrader) - [Related Materials](https://www.sigmaaldrich.com#related-materials) ## [](https://www.sigmaaldrich.com)Targeted Protein Degradation Protein degradation refers to the process by which proteins are broken down into smaller peptides or amino acids. Protein degraders are molecules or compounds that facilitate or enhance this degradation process. Targeted protein degradation is a novel strategy that uses small molecules to hijack endogenous proteolysis systems to degrade disease-relevant proteins. Reducing protein abundance in cells, phenotypes similar to gene-editing approaches (e.g. CRISPR-Cas9) can be achieved but with the advantages that come with small molecules. Not only is this of interest as a research tool to study the impact of selective protein knockdowns, but it has quickly been adopted by the global drug discovery community for its advantages over occupancy-based inhibition and drugging ~80% of proteins traditionally intractable to small molecules. Agents used in these approaches are called protein degraders, such as proteolysis-targeting chimeras (PROTAC® degraders) or molecular glues. Heterobifunctional protein degraders contain a target-binding warhead on one end and an E3 ubiquitin ligase-targeting ligand on the other, connected by a linker in the middle (__Figure 1__). When the degrader is applied, it recruits the target to the E3 ligase. Once in proximity of the E3 ligase, the target is polyubiquitinated, flagging it for degradation via the proteasome.1-3 __PROTAC____®__ __is a registered trademark of Arvinas Operations, Inc., and is used under license.__  __Figure 1.__Targeted protein degradation via proteolysis-targeting chimeras (PROTACs) ## [](https://www.sigmaaldrich.com)Challenges for Protein Degrader Synthesis The design of degraders is challenging as slight alterations in structure can alter ternary complex formation and subsequent degradation.4 The 3D model in __Figure 2__ based on PDB 5T35 illustrates the importance of careful design to achieve binding to two disparate proteins (the target and E3 ligase) and the establishment of a protein–protein interface. Even with advances in computational chemistry, degrader design is still largely an empirical process where researchers generate libraries of degraders, taking a modular approach to varying the ligands, linkers, and exit vectors, an intense upfront chemistry endeavor.4,6  __Figure 2.a)__ Chemical structure of representative PROTAC MZ1 highlighting target ligand, E3 ligase ligand, linker, and exit vector. __b)__ Degrader structure impacts ternary complex formation, illustrated with MZ16. __c)__ Empirical design requires the generation of libraries to test on case-by-case basis. ## [](https://www.sigmaaldrich.com)Streamlined Synthesis of Heterobifunctional Degrader Libraries Our protein degrader building blocks are the easiest way to generate heterobifunctional degrader screening libraries from one starting target ligand to expedite degrader hit discovery. Within this building block collection that comprises all the components to construct degraders, our ligand–linker conjugates eliminate upfront synthetic steps, requiring only the chemistry to link a target ligand on the terminal functional group (__Figure 3__). Moreover, if the same terminal chemistry is selected, a chemist can simultaneously react 50+ ligand–linker conjugates with one starting target ligand in parallel to generate an initial screening library.  __Figure 3.__Ligand–linker conjugates ## [](https://www.sigmaaldrich.com)Diversity of the Ligand - Linker Conjugates Our suite of ligand–linker conjugates contains strategic combinations of E3 ligands, exit vectors, linkers, and terminal chemistry. E3 ligase recruiters and ligands: While more E3 ligases are being researched for targeted protein degradation, a handful are used most often in the development of protein degraders.7 Our conjugates include ligands and varied exit vectors for the validated E3 ligases CRBN, VHL, IAP, and RNF4 (__Figure 4__). Linkers: Alkyl and PEG linkers are excellent starters to sample a range of hydrophobicity, flexibility, and lengths. In addition, we offer many “mixed”8 and rigid9–11 linkers to achieve diverse linker properties in your library (__Figure 3__). Terminal chemistry: A variety of popular functional groups are available for linking the target warhead; our largest group includes terminal amines (__Figure 3__). ## [](https://www.sigmaaldrich.com)Advantages - __Synthetic time-saver__: Ligand–linker conjugates simplify synthesis of single degraders and parallel synthesis for library construction - __Molecule design__: Permutations of highest-interest E3 ligands, exit vectors, and linkers within the conjugates ease upfront combinatorial library design - __Compatibility__: Linkers conjugate to common functional groups present on target ligands - __SAR__: Strategic component variation built into the ligand–linker conjugates provides an upfront glimpse at SAR for informed optimization  __Figure 4.__E3 Ligase ligands featured in conjugates ## [](https://www.sigmaaldrich.com)LET US HELP YOU BUILD YOUR DEGRADER LIBRARY BASED ON WHAT IS MOST IMPORTANT TO YOU Reach out to your MilliporeSigma technical specialist or SigmaAldrich.com/techservice for a sortable list or structure data file of all synthesis products, including 150+ ligand–linker conjugates, 250+ heterobifunctional linkers, 20+ ligands, and related probe compounds. ## Related Articles - [Degrader Building Blocks with IAP In Silico-Derived Ligands](https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/protein-degradation/degrader-building-blocks-with-inhibitor-of-apoptosis-protein) - [Accelerating IAP-Based Protein Degrader Discovery with Novel Ligand Library](https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/lead-discovery/accelerating-iap-based-protein-degrader-discovery-with-novel-ligand-library) ## Webinars - [Targeted Protein Degradation Using Small Molecules, Alessio Ciulli](https://www.chemistryworld.com/webinars/targeted-protein-degradation-using-small-molecules/3009699.article) - [Developing Small-molecule Degraders Using Chemoproteomics, Nathanael Gray](https://www.chemistryworld.com/webinars/developing-small-molecule-degraders-using-chemoproteomics/4012465.article) ## Related Materials Sorry, an unexpected error has occurred Response not successful: Received status code 500 ### References 1\. Fisher SL, Phillips AJ. 2018. Targeted protein degradation and the enzymology of degraders. Current Opinion in Chemical Biology. 4447-55. [https://doi.org/10.1016/j.cbpa.2018.05.004](https://doi.org/10.1016/j.cbpa.2018.05.004) 2\. Cromm PM, Crews CM. 2017. Targeted Protein Degradation: from Chemical Biology to Drug Discovery. Cell Chemical Biology. 24(9):1181-1190. [https://doi.org/10.1016/j.chembiol.2017.05.024](https://doi.org/10.1016/j.chembiol.2017.05.024) 3\. Bondeson DP, Smith BE, Burslem GM, Buhimschi AD, Hines J, Jaime-Figueroa S, Wang J, Hamman BD, Ishchenko A, Crews CM. 2018. Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead. Cell Chemical Biology. 25(1):78-87.e5. [https://doi.org/10.1016/j.chembiol.2017.09.010](https://doi.org/10.1016/j.chembiol.2017.09.010) 4\. Hughes S, Ciulli A. 2017. Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders. 61(5):505-516. [https://doi.org/10.1042/ebc20170041](https://doi.org/10.1042/ebc20170041) 5\. Gadd MS, Testa A, Lucas X, Chan K, Chen W, Lamont DJ, Zengerle M, Ciulli A. 2017. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat Chem Biol. 13(5):514-521. [https://doi.org/10.1038/nchembio.2329](https://doi.org/10.1038/nchembio.2329) 6\. Schlesiger S, Toure M, Wilke K, Huck B. 2019. Accelerating the Discovery of Next-Generation Small-Molecule Protein Degraders. . Aldrichimica Acta.(52):35–47. [https://www.sigmaaldrich.com/deepweb/assets/sigmaaldrich/marketing/global/documents/377/287/acta-52-ms.pdf](https://www.sigmaaldrich.com/deepweb/assets/sigmaaldrich/marketing/global/documents/377/287/acta-52-ms.pdf) 7\. Ishida T, Ciulli A. 2021. E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones. SLAS DISCOVERY: Advancing the Science of Drug Discovery. 26(4):484-502. [https://doi.org/10.1177/2472555220965528](https://doi.org/10.1177/2472555220965528) 8\. Lai AC, Toure M, Hellerschmied D, Salami J, Jaime-Figueroa S, Ko E, Hines J, Crews CM. 2016. Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL. Angew. Chem. Int. Ed.. 55(2):807-810. [https://doi.org/10.1002/anie.201507634](https://doi.org/10.1002/anie.201507634) 9\. Bond MJ, Crews CM. Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation. RSC Chem. Biol.. 2(3):725-742. [https://doi.org/10.1039/d1cb00011j](https://doi.org/10.1039/d1cb00011j) 10\. Atilaw Y, Poongavanam V, Svensson Nilsson C, Nguyen D, Giese A, Meibom D, Erdelyi M, Kihlberg J. 2021. Solution Conformations Shed Light on PROTAC Cell Permeability. ACS Med. Chem. Lett.. 12(1):107-114. [https://doi.org/10.1021/acsmedchemlett.0c00556](https://doi.org/10.1021/acsmedchemlett.0c00556) 11\. Xiang W, Zhao L, Han X, Qin C, Miao B, McEachern D, Wang Y, Metwally H, Kirchhoff PD, Wang L, et al. 2021. Discovery of ARD-2585 as an Exceptionally Potent and Orally Active PROTAC Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer. J. Med. Chem.. 64(18):13487-13509. [https://doi.org/10.1021/acs.jmedchem.1c00900](https://doi.org/10.1021/acs.jmedchem.1c00900) 12\. Buckley DL, Raina K, Darricarrere N, Hines J, Gustafson JL, Smith IE, Miah AH, Harling JD, Crews CM. 2015. HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins. ACS Chem. Biol.. 10(8):1831-1837. [https://doi.org/10.1021/acschembio.5b00442](https://doi.org/10.1021/acschembio.5b00442) 13\. Jaime-Figueroa S, Buhimschi AD, Toure M, Hines J, Crews CM. 2020. Design, synthesis and biological evaluation of Proteolysis Targeting Chimeras (PROTACs) as a BTK degraders with improved pharmacokinetic properties. Bioorganic & Medicinal Chemistry Letters. 30(3):126877. [https://doi.org/10.1016/j.bmcl.2019.126877](https://doi.org/10.1016/j.bmcl.2019.126877) 14\. Steinebach C, Ng YLD, Sosi? I, Lee C, Chen S, Lindner S, Vu LP, Bricelj A, Haschemi R, Monschke M, et al. Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders. Chem. Sci.. 11(13):3474-3486. [https://doi.org/10.1039/d0sc00167h](https://doi.org/10.1039/d0sc00167h) 15\. Smith BE, Wang SL, Jaime-Figueroa S, Harbin A, Wang J, Hamman BD, Crews CM. 2019. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nat Commun. 10(1): [https://doi.org/10.1038/s41467-018-08027-7](https://doi.org/10.1038/s41467-018-08027-7) 16\. Ward CC, Kleinman JI, Brittain SM, Lee PS, Chung CYS, Kim K, Petri Y, Thomas JR, Tallarico JA, McKenna JM, et al. 2019. Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications. ACS Chem. Biol.. 14(11):2430-2440. [https://doi.org/10.1021/acschembio.8b01083](https://doi.org/10.1021/acschembio.8b01083) 17\. Ohoka N, Okuhira K, Ito M, Nagai K, Shibata N, Hattori T, Ujikawa O, Shimokawa K, Sano O, Koyama R, et al. 2017. In Vivo Knockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs). Journal of Biological Chemistry. 292(11):4556-4570. [https://doi.org/10.1074/jbc.m116.768853](https://doi.org/10.1074/jbc.m116.768853) 18\. Naito M, Ohoka N, Shibata N. 2019. SNIPERs?Hijacking IAP activity to induce protein degradation. Drug Discovery Today: Technologies. 3135-42. [https://doi.org/10.1016/j.ddtec.2018.12.002](https://doi.org/10.1016/j.ddtec.2018.12.002) __Related Articles__ - [Accelerating Protein Degrader Discovery with IAP](https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/lead-discovery/accelerating-iap-based-protein-degrader-discovery-with-novel-ligand-library) - [Degrader Building Blocks with IAP In Silico-Derived Ligands](https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/protein-degradation/degrader-building-blocks-with-inhibitor-of-apoptosis-protein) - [PROTAC Synthesis Kits for Targeted Protein Degradation](https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/chemistry-and-synthesis/protein-degradation/protac-synthesis-kits-for-targeted-protein-degradation) __Related Product Categories__ - [Click Chemistry Reagents Overview](https://www.sigmaaldrich.com/US/en/products/chemistry-and-biochemicals/chemical-biology/click-chemistry-reagents) - [Chemical Biology](https://www.sigmaaldrich.com/US/en/products/chemistry-and-biochemicals/chemical-biology) - [Protein Degrader Building Blocks](https://www.sigmaaldrich.com/US/en/products/chemistry-and-biochemicals/chemical-biology/protein-degrader-building-blocks) - [Synthesis Enabling Tools](https://www.sigmaaldrich.com/US/en/products/chemistry-and-biochemicals/synthesis-enabling-tools) - [Automated Chemical Synthesis](https://www.sigmaaldrich.com/US/en/products/chemistry-and-biochemicals/synthesis-enabling-tools/automated-chemical-synthesis) Top __Sign In To Continue__ To continue reading please sign in or create an account. 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[Interrogation of Protein Pathways](https://www.sigmaaldrich.com/US/en/applications/protein-biology/interrogation-protein-pathways) - [Lysis & Protein Extraction](https://www.sigmaaldrich.com/US/en/applications/protein-biology/lysis-and-protein-extraction) - [Protein & Nucleic Acid Interactions](https://www.sigmaaldrich.com/US/en/applications/protein-biology/protein-and-nucleic-acid-interactions) - [Protein Concentration & Buffer Exchange](https://www.sigmaaldrich.com/US/en/applications/protein-biology/protein-concentration-and-buffer-exchange) - [Protein Expression](https://www.sigmaaldrich.com/US/en/applications/protein-biology/protein-expression) - [Protein Labeling & Modification](https://www.sigmaaldrich.com/US/en/applications/protein-biology/protein-labeling-and-modification) - [Protein Pulldown](https://www.sigmaaldrich.com/US/en/applications/protein-biology/protein-pulldown) - [Protein Purification](https://www.sigmaaldrich.com/US/en/applications/protein-biology/protein-purification) - 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Services - [Contract Manufacturing](https://www.sigmaaldrich.com/US/en/services/contract-manufacturing) - [ADC & Bioconjugation](https://www.sigmaaldrich.com/US/en/services/contract-manufacturing/adc-bioconjugation) - [Diagnostic OEM & CMO Services](https://www.sigmaaldrich.com/US/en/services/ivd-development-manufacturing/diagnostic-oem-cmo) - [mRNA & LNP](https://www.sigmaaldrich.com/US/en/services/contract-manufacturing/mrna-and-lnp-formulation-ctdmo-services) - [Lipids CDMO Services](https://www.sigmaaldrich.com/US/en/services/contract-manufacturing/mrna-and-lnp-formulation-ctdmo-services/lipids-cdmo-services) - [Lipid Nanoparticle CDMO Service](https://www.sigmaaldrich.com/US/en/services/contract-manufacturing/mrna-and-lnp-formulation-ctdmo-services/lipid-nanoparticle-cdmo-services) - [Small Molecule](https://www.sigmaaldrich.com/US/en/services/contract-manufacturing/small-molecule) - [Activated Polyethylene Glycol (PEGs)](https://www.sigmaaldrich.com/US/en/services/contract-manufacturing/peg) - 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