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Although click reactions have been widely applied to prepare highly functionalized biomolecules, most of them are limited to two\u2010component reactions, restricting the creation of more complex structures. Here, we developed a convenient multi\u2010component assembly strategy via strain\u2010promoted alkyne\u2013nitrone cycloaddition (SPANC), which can be extended to a 3\u2010component reaction when combined with nitrone formation. Using the 2\u2010component assembly, we demonstrated the targeted protein degradation with both preassembled and in\u2010cell assembled PROTACs. This strategy was also applied to facilitate the screening of E3 ligases in PROTACs and the preparation of various biological probes. Moreover, the 3\u2010component assembly, via sequential nitrone formation and SPANC, enabled the synthesis of trifunctional 3\u2010component PROTACs. The <jats:italic>N<\/jats:italic>\u2010substituent, serving as an additional functional moiety, was designed as a photocage for sterically controlling PROTAC activity. The 3\u2010component assembly can be further modified to provide additional control or enhance the cell\u2010targeting ability of PROTACs. In short, our multi\u2010component SPANC assembly strategy offers a modular and versatile synthetic platform for creating multi\u2010functional PROTACs and biological probes.<\/jats:p>","DOI":"10.1002\/chem.202403184","type":"journal-article","created":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T12:44:31Z","timestamp":1733489071000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Utilizing Alkyne\u2010Nitrone Cycloaddition for the Convenient Multi\u2010Component Assembly of Protein Degraders and Biological Probes"],"prefix":"10.1002","volume":"31","author":[{"given":"Shiou\u2010Ting","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Chemistry National Taiwan University  Taipei 106319 Taiwan R.O.C."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4690-3438","authenticated-orcid":false,"given":"Chien\u2010Hua","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry National Taiwan University  Taipei 106319 Taiwan R.O.C."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai\u2010Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemistry National Taiwan University  Taipei 106319 Taiwan R.O.C."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsung\u2010Shing","family":"Andrew Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry National Taiwan University  Taipei 106319 Taiwan R.O.C."},{"name":"Center for Emerging Material and Advanced Devices National Taiwan University  Taipei 106319 Taiwan R.O.C."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,16]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00371-6"},{"key":"e_1_2_8_2_1","unstructured":"\u00a0"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201507634"},{"key":"e_1_2_8_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2017.09.010"},{"key":"e_1_2_8_5_1","unstructured":"\u00a0"},{"key":"e_1_2_8_6_2","doi-asserted-by":"publisher","DOI":"10.37349\/etat.2020.00018"},{"key":"e_1_2_8_7_2","doi-asserted-by":"publisher","DOI":"10.37349\/etat.2020.00023"},{"key":"e_1_2_8_8_1","unstructured":"\u00a0"},{"key":"e_1_2_8_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b01781"},{"key":"e_1_2_8_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.0c00140"},{"key":"e_1_2_8_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202200275"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00302"},{"key":"e_1_2_8_13_1","unstructured":"\u00a0"},{"key":"e_1_2_8_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b06422"},{"key":"e_1_2_8_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b12718"},{"key":"e_1_2_8_16_1","unstructured":"\u00a0"},{"key":"e_1_2_8_17_2","doi-asserted-by":"publisher","DOI":"10.1039\/D2CC03092F"},{"key":"e_1_2_8_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.9b00713"},{"key":"e_1_2_8_19_1","unstructured":"\u00a0"},{"key":"e_1_2_8_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202306824"},{"key":"e_1_2_8_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abq2216"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c00451"},{"key":"e_1_2_8_23_1","unstructured":"\u00a0"},{"key":"e_1_2_8_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-021-00878-4"},{"key":"e_1_2_8_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00649"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115497"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c03852"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.6b00280"},{"key":"e_1_2_8_29_1","unstructured":"\u00a0"},{"key":"e_1_2_8_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.3c00199"},{"key":"e_1_2_8_31_2","author":"Giardina S. 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