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Herein, we present a novel concept exploiting the thiol gradient phenomena to design a new class of cleavable linker with no disulfide bond. To support the concept, an electron\u2010deficient sulfonamide\u2010based cleavable linker amenable to conjugation of drug molecules with targeting agents, was developed. Modulating the electron\u2010withdrawing nature of the aryl sulfonamide was critical to the balance between the stability and drug release. Favorable stability and payload release in human serum under physiologically relevant thiol concentrations was demonstrated with two potent cytotoxics. Intracellular payload release was further validated in cell\u2010based assay in context of antibody\u2010drug conjugate generated from monoclonal antibody and sulfonamide containing linker. To support the proposed release mechanism, possible downstream by\u2010products formed from the drug\u2010linker adduct were characterized.<\/jats:p>","DOI":"10.1002\/cbic.202400826","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T22:16:35Z","timestamp":1729289795000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Novel Concept for Cleavable Linkers Applicable to Conjugation Chemistry \u2013 Design, Synthesis and Characterization"],"prefix":"10.1002","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2173-9405","authenticated-orcid":false,"given":"Utpal","family":"Majumder","sequence":"first","affiliation":[{"name":"Oncology Product Creation Unit, Eisai Inc.  35\u2005Cambridgepark Drive Cambridge MA-02140 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaojie","family":"Zhu","sequence":"additional","affiliation":[{"name":"Oncology 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