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IMiDs bind cereblon (CRBN), an adaptor for the CUL4\u2010DDB1\u2010RBX1 E3 ligase to change its substrate specificity and induce degradation of \u2018neosubstrate\u2019 transcription factors that are essential to MM cells. Mechanistic studies to date have largely focussed on mediators of therapeutic activity and insight into clinical IMiD toxicities is less developed. We adopted BioID2\u2010dependent proximity labelling (BioID2\u2010CRBN) to characterise the CRBN interactome in the presence and absence of various IMiDs and the proteasome inhibitor, bortezomib. We aimed to leverage this technology to further map CRBN interactions beyond what has been achieved by conventional proteomic techniques. In support of this approach, analysis of cells expressing BioID2\u2010CRBN following IMiD treatment displayed biotinylation of known CRBN interactors and neosubstrates. We observed that bortezomib alone significantly modifies the CRBN interactome. Proximity labelling also suggested that IMiDs augment the interaction between CRBN and proteins that are not degraded, thus designating \u2018neointeractors\u2019 distinct from previously disclosed \u2018neosubstrates\u2019. Here we identify Non\u2010Muscle Myosin Heavy Chain IIA (MYH9) as a putative CRBN neointeractor that may contribute to the haematological toxicity of IMiDs. These studies provide proof of concept for proximity labelling technologies in the mechanistic profiling of IMiDs and related E3\u2010ligase\u2010modulating drugs.<\/jats:p>","DOI":"10.1111\/febs.17196","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T10:01:34Z","timestamp":1720432894000},"page":"4892-4912","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Mapping the\n                    <scp>IM<\/scp>\n                    i\n                    <scp>D<\/scp>\n                    \u2010dependent cereblon interactome using\n                    <scp>B<\/scp>\n                    io\n                    <scp>ID<\/scp>\n                    \u2010proximity labelling"],"prefix":"10.1111","volume":"291","author":[{"given":"Matteo","family":"Costacurta","sequence":"first","affiliation":[{"name":"Monash Haematology Monash Health  Clayton Australia"},{"name":"Blood Cancer Therapeutics 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