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While the discovery of heterobifunctional CIPs is expedited by rational design strategies, molecular glues have relied predominantly on serendipity. We hypothesized that preexisting ligands could be systematically decorated with chemical modifications to discover compounds that recruit proteins to a composite protein\u2013ligand interface. Using sulfur(VI) fluoride exchange-based high-throughput chemistry (HTC) to install 3,163 structurally diverse building blocks onto ENL (eleven-nineteen leukemia) and BRD4 (bromodomain-containing protein 4) ligands, we screened each analog for degrader activity. This revealed dHTC1, an ENL degrader that recruits CRL4\n                    <jats:sup>CRBN<\/jats:sup>\n                    complex through an extended interface of protein\u2013protein contacts and only engages CRBN after pre-forming the ENL:dHTC1 complex. We also identified dHTC3, a molecular glue that selectively dimerizes BRD4 bromodomain 1 to SCF\n                    <jats:sup>FBXO3<\/jats:sup>\n                    , an E3 ligase not previously accessible for chemical rewiring. Altogether, this study introduces HTC as a facile tool to discover new CIPs and new effectors for proximity pharmacology.\n                  <\/jats:p>","DOI":"10.1038\/s41589-025-02137-2","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T10:02:48Z","timestamp":1771236168000},"page":"1540-1552","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["High-throughput ligand diversification to discover chemical inducers of proximity"],"prefix":"10.1038","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1664-1091","authenticated-orcid":false,"given":"James B.","family":"Shaum","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4391-6393","authenticated-orcid":false,"given":"Miquel","family":"Mu\u00f1oz i 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M.A.E., E.A.S. and J.B.S. are inventors on a patent application related to dHTC1. M.A.E. holds equity in Nexo Therapeutics and serves on their scientific advisory board (SAB). G.E.W. is a scientific founder and shareholder of Proxygen and Solgate and is on the SAB of Proxygen. He also holds equity in Cellgate Therapeutics and Nexo Therapeutics and serves on the SAB of Nexo Therapeutics. The G.E.W. lab has received research funding from Pfizer. E.S.F. is a founder, SAB member and equity holder of Civetta Therapeutics, Proximity Therapeutics, Neomorph (also on the board of directors), Stelexis Biosciences and Anvia Therapeutics (also on the board of directors). He is an equity holder and SAB member of Avilar Therapeutics, Photys Therapeutics and Ajax Therapeutics and an equity holder in Lighthorse Therapeutics and CPD4 (also on the board of directors). E.S.F. is a consultant to Novartis, EcoR1 Capital and Deerfield. 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